Placental Corticotropin-releasing Hormone Research Articles

Leukemia inhibitory factor induces corticotropin-releasing hormone in mouse trophoblast stem cells

Previous studies have shown that some inflammatory cytokines promote the expression of corticotropin-releasing hormone (CRH) in trophoblasts during pregnancy and that placental CRH could induce the production of adrenocorticotropic hormone (ACTH) in humans. However, whether the same is true in rodent placenta remains unclear. In this study, we examined the effect of pro-inflammatory cytokine LIF on the induction of CRH in mouse trophoblast stem cells (mTSCs). During differentiation, the CRH levels in mTSCs gradually increased. On days 3 and 5 after LIF supplementation, Crh expression in the differentiated mTSCs was significantly increased with LIF treatment than those without LIF treatment. Moreover, the CRH concentration in the culture media increased. Thereafter, we examined the contribution of the downstream pathways of LIF to CRH induction in differentiated mTSCs. The LIF-induced upregulation of CRH was attenuated by inhibition of PI3K/AKT and MAPK phosphorylation but not by inhibition of JAK/STAT3. Therefore, in mTSCs, LIF increased Crh expression through activation of the PI3K/AKT and MAPK pathways but not by the JAK/STAT3 pathway. The present study suggests that mTSC is an ideal in vitro model for studying regulation and function of placental CRH.

Interaction between the functional SNP rs2070951 in NR3C2 gene and high levels of plasma corticotropin-releasing hormone associates to postpartum depression.

Postpartum depression (PPD) is a common mood disorder that occurs after delivery with a prevalence of approximately 10%. Recent reports have related placental corticotropin-releasing hormone (pCRH) to postpartum depressive symptoms. The aim of this study was to determine whether pCRH, ACTH, and cortisol (measured 48h after delivery) and glucocorticoid and mineralocorticoid receptor genotypes (NR3C1 and NR3C2) and their interaction are associated with PPD. A longitudinal 32-week prospective study of five hundred twenty-five Caucasian depression-free women that were recruited from obstetric units at two Spanish general hospitals immediately after delivery. Of the women included in the sample, forty-two (8%) developed PPD. A strong association between PPD and the interaction between the pCRH and NR3C2 rs2070951 genotype was observed. The mean level of pCRH in rs2070951GG carriers with PPD was 56% higher than the mean in the CG and CC genotype groups (P < 0.00005). Carriers of the rs2070951GG genotype with high levels of pCRH had a higher risk of developing PPD (OR = 1.020, 95% CI 1.007-1.034, P = 0.002). This association remained even after controlling for variables such as neuroticism, obstetric complications and the number of stressful life events during pregnancy. There is an important interaction between pCRH 48h postpartum and the NR3C2 rs2070951GG genotype. This interaction moderately associates with the presence of PPD. These results may open a new line of research and, if confirmed in other settings, will help to identify better risk predictors and the treatment for PPD.

Transcriptional co-activator TAZ controls extravillous trophoblast formation and function in the developing human placenta

The most adverse perinatal outcome of intrahepatic cholestasis of pregnancy (ICP) is sudden fetal death related to acute fetoplacental hypoxia. Corticotrophin-releasing hormone (CRH), urocortin (UCN), and Wolfram syndrome 1 (WFS1) proteins may have a compensatory response to hypoxic stress.A total of 108 singleton pregnant women were divided into three groups: control, late-onset ICP, and early-onset ICP. Enzyme-linked immunosorbent assays were used to detected maternal serum CRH, UCN, and WFS1 levels. Western blotting and real-time polymerase chain reaction were conducted to quantify placental protein and mRNA levels of CRH, UCN, and WFS1. Pearson correlation scatterplots and Pearson correlation matrix were employed to testify the correlation.Placental WFS1 had a positive relation with placental UCN (r = 0.69, P < 0.05) and serum UCN (r = 0.36, P < 0.05). Placental CRH was positively correlated with maternal serum CRH (r = 0.53, P < 0.05). Maternal serum and placental levels of CRH, UCN, and WFS1 significantly increased in the early-onset ICP group compared with the control group (P < 0.05). Placental levels of UCN and WFS1 in the early-onset ICP group were significantly elevated and higher in comparison with the late-onset ICP group (P < 0.05). However, the transcriptional levels of CRH, UCN, and WFS1 were impaired in the early-onset ICP group.Our study revealed that transcription and translation of WFS1, CRH, and UCN were altered during pregnancies complicated by early-onset ICP. This disrupted compensatory response mediated by WFS1 and CRH family peptides in early-onset ICP may play a significant role in the pathogenesis of sudden fetal death in acute fetal hypoxia.

Pericytes mapping in bovine placenta

The most adverse perinatal outcome of intrahepatic cholestasis of pregnancy (ICP) is sudden fetal death related to acute fetoplacental hypoxia. Corticotrophin-releasing hormone (CRH), urocortin (UCN), and Wolfram syndrome 1 (WFS1) proteins may have a compensatory response to hypoxic stress.A total of 108 singleton pregnant women were divided into three groups: control, late-onset ICP, and early-onset ICP. Enzyme-linked immunosorbent assays were used to detected maternal serum CRH, UCN, and WFS1 levels. Western blotting and real-time polymerase chain reaction were conducted to quantify placental protein and mRNA levels of CRH, UCN, and WFS1. Pearson correlation scatterplots and Pearson correlation matrix were employed to testify the correlation.Placental WFS1 had a positive relation with placental UCN (r = 0.69, P < 0.05) and serum UCN (r = 0.36, P < 0.05). Placental CRH was positively correlated with maternal serum CRH (r = 0.53, P < 0.05). Maternal serum and placental levels of CRH, UCN, and WFS1 significantly increased in the early-onset ICP group compared with the control group (P < 0.05). Placental levels of UCN and WFS1 in the early-onset ICP group were significantly elevated and higher in comparison with the late-onset ICP group (P < 0.05). However, the transcriptional levels of CRH, UCN, and WFS1 were impaired in the early-onset ICP group.Our study revealed that transcription and translation of WFS1, CRH, and UCN were altered during pregnancies complicated by early-onset ICP. This disrupted compensatory response mediated by WFS1 and CRH family peptides in early-onset ICP may play a significant role in the pathogenesis of sudden fetal death in acute fetal hypoxia.

Disrupted compensatory response mediated by Wolfram syndrome 1 protein and corticotrophin-releasing hormone family peptides in early-onset intrahepatic cholestasis pregnancy

IntroductionThe most adverse perinatal outcome of intrahepatic cholestasis of pregnancy (ICP) is sudden fetal death related to acute fetoplacental hypoxia. Corticotrophin-releasing hormone (CRH), urocortin (UCN), and Wolfram syndrome 1 (WFS1) proteins may have a compensatory response to hypoxic stress. MethodsA total of 108 singleton pregnant women were divided into three groups: control, late-onset ICP, and early-onset ICP. Enzyme-linked immunosorbent assays were used to detected maternal serum CRH, UCN, and WFS1 levels. Western blotting and real-time polymerase chain reaction were conducted to quantify placental protein and mRNA levels of CRH, UCN, and WFS1. Pearson correlation scatterplots and Pearson correlation matrix were employed to testify the correlation. ResultsPlacental WFS1 had a positive relation with placental UCN (r = 0.69, P < 0.05) and serum UCN (r = 0.36, P < 0.05). Placental CRH was positively correlated with maternal serum CRH (r = 0.53, P < 0.05). Maternal serum and placental levels of CRH, UCN, and WFS1 significantly increased in the early-onset ICP group compared with the control group (P < 0.05). Placental levels of UCN and WFS1 in the early-onset ICP group were significantly elevated and higher in comparison with the late-onset ICP group (P < 0.05). However, the transcriptional levels of CRH, UCN, and WFS1 were impaired in the early-onset ICP group. DiscussionOur study revealed that transcription and translation of WFS1, CRH, and UCN were altered during pregnancies complicated by early-onset ICP. This disrupted compensatory response mediated by WFS1 and CRH family peptides in early-onset ICP may play a significant role in the pathogenesis of sudden fetal death in acute fetal hypoxia.

Biomarkers in the Hypothalamus-pituitary-adrenal Axis Were Associated with Maternal Psychosocial Stress and Choline Intake and Status During Pregnancy (P11-011-19)

ObjectivesMaternal psychosocial stress during pregnancy can lead to heightened activity of the hypothalamus-pituitary-adrenal (HPA) axis, increasing the risk of pre-term birth, intrauterine restriction, and preeclampsia. Maternal dietary intakes and nutrition status modify epigenetic marks in the placental and fetal HPA axis, which may then counter the negative influence of maternal stress. This study aims to determine the correlation of maternal psychosocial stress and nutrient intakes with biomarkers of HPA axis activity in human pregnancies. MethodsPregnant women (n = 60) were recruited to this observational study. Psychosocial stress survey, dietary recalls and blood samples were obtained in the 3rd trimester. Placentas and cord blood were retrieved at delivery. ResultsMaternal financial stress, neighborhood stress, and anxiety were positively or tended to be positively associated with maternal blood cortisol levels (P = 0.01-0.08), although none of the psychosocial stress measurements were correlated with placental corticotropin-releasing hormone (CRH), glucocorticoid receptor (NR3C1), or 11β-hydroxysteroid dehydrogenase (11BHSD) expression. Placental NR3C1 expression was positively associated with birth weight (r = 0.42, P = 0.02) while placental CRH was negatively associated with gestational length (r = –0.45, P = 0.01). Overall dietary quality as measured by the Healthy Eating Index (HEI) was not associated with psychosocial stress or related biomarkers, while intakes of the methyl donor choline (r = 0.46, P = 0.04) and omega-3 fatty acids (r = 0.47, P = 0.03) were positively associated with placental NR3C1 expression. Placental choline content was also positively associated with NR3C1 expression (r = 0.39, P = 0.04) and negatively associated with maternal neighborhood stress (r = –0.72, P = 0.02). ConclusionsIn summary, these data suggest that maternal psychosocial stress may adversely affect HPA axis functioning during pregnancy, whereas choline and other nutrients have the potential to counteract some of the impacts of psychosocial stress. Funding SourcesCUNY Interdisciplinary Research Grant.

Can placental corticotropin-releasing hormone inform timing of antenatal corticosteroid administration?

Can placental corticotropin-releasing hormone inform timing of antenatal corticosteroid administration?

Vitamin D stimulates multiple microRNAs to inhibit CRH and other pro-labor genes in human placenta.

Maternal vitamin D deficiency is linked to adverse pregnancy outcomes including spontaneous preterm birth (SPB). Placental corticotropin-releasing hormone (CRH) has been proposed to be part of a clock that governs the length of gestation in humans, with elevated maternal serum levels predicting early delivery. In this study, we test the hypothesis that vitamin D could contribute to the prevention of preterm labor by inhibiting CRH and other pro-labor mediators. The biological activity of vitamin D occurs via two pathways: non-genomic and genomic responses, both of which involve binding of 1,25-dihydroxyvitamin D (1,25(OH)2D), the active metabolite of vitamin D binding to the vitamin D receptor (VDR). By using chromatin immunoprecipitation followed by sequencing (ChIP-seq), we found that 1,25(OH)2D stimulates association of VDR with a number of miRNA genes including MIR181B2 and MIR26B, and their mature products miR-181b-5p and miR-26b-5p are predicted to target CRH and cyclooxygenase-2 (COX-2) mRNA at 3′-untranslated region (UTR), respectively. We performed RT-qPCR analysis to validate that expression of mature miR-181b-5p and miR-26b-5p in term human syncytiotrophoblast increased in response to treatment with 1,25(OH)2D. miR-181b-5p- or miR-26b-5p-mediated inhibition of CRH or COX-2 was further assessed by the use of miRNA mimics/inhibitors and a luciferase reporter assay. Taken together, this study has identified novel mechanisms by which vitamin D downregulates pro-labor genes and could lower the risk of preterm delivery.

Anthropoid primate–specific retroviral element THE1B controls expression of CRH in placenta and alters gestation length

Pregnancy and parturition are intricately regulated to ensure successful reproductive outcomes. However, the factors that control gestational length in humans and other anthropoid primates remain poorly defined. Here, we show the endogenous retroviral long terminal repeat transposon-like human element 1B (THE1B) selectively controls placental expression of corticotropin-releasing hormone (CRH) that, in turn, influences gestational length and birth timing. Placental expression of CRH and subsequently prolonged gestational length were found in two independent strains of transgenic mice carrying a 180-kb human bacterial artificial chromosome (BAC) DNA that contained the full length of CRH and extended flanking regions, including THE1B. Restricted deletion of THE1B silenced placental CRH expression and normalized birth timing in these transgenic lines. Furthermore, we revealed an interaction at the 5′ insertion site of THE1B with distal-less homeobox 3 (DLX3), a transcription factor expressed in placenta. Together, these findings suggest that retroviral insertion of THE1B into the anthropoid primate genome may have initiated expression of CRH in placental syncytiotrophoblasts via DLX3 and that this placental CRH is sufficient to alter the timing of birth.

Pregnancy anxiety predicts shorter gestation in Latina and non-Latina white women: The role of placental corticotrophin-releasing hormone

ObjectivePrevious research has shown that a woman’s anxiety about her pregnancy predicts gestational length. Placental corticotrophin-releasing hormone (CRH) is a stress-responsive peptide proposed as a mechanism. We examined placental CRH as a physiological mediator of the association between pregnancy anxiety and gestational length in Latina and non-Latina White women to replicate evidence of associations between pregnancy anxiety, placental CRH and gestational length; to test whether placental CRH levels or changes mediate effects of pregnancy anxiety on gestational length; to examine ethnic differences in pregnancy anxiety, placental CRH, and gestational length; and to explore whether the effects of pregnancy anxiety on gestational length as mediated by placental CRH vary by ethnicity. MethodsIn a prospective study of 337 pregnant Latina and non-Latina White women, participants completed in-person interviews that included a 10-item measure of pregnancy anxiety and provided blood samples assayed using radioimmunoassay at three timepoints (19, 25, and 31 weeks gestation). ResultsPregnancy anxiety at 19 and 31 weeks and levels of placental CRH at 31 weeks predicted gestational length. Tests of indirect effects were consistent with mediation such that both pregnancy anxiety at 19 weeks and increases from 19 to 31 weeks predicted placental CRH at 31 weeks, which in turn predicted gestational length. Tests of moderated mediation by ethnicity showed that the mediated effect of placental CRH at 31 weeks was significant for Latinas only. ConclusionsThese findings add to growing evidence of the involvement of pregnancy anxiety in the timing of birth, address mechanisms, and suggest possible ethnic differences.

Prenatal CRH: An integrating signal of fetal distress.

Corticotropin-releasing hormone (CRH) is distributed throughout the brain and in peripheral sites but primarily is localized in the paraventricular nucleus of the hypothalamus. It is a "master" stress hormone that is responsible for the synthesis of proopiomelanocortin (POMC) in the anterior pituitary gland. Behaviorally active peptide hormones, including adrenocorticotropin hormone (ACTH) and B-endorphin, are liberated from POMC by enzymes to activate critical processes during stress. CRH is not detectable in the circulation even during extreme stress. However, during human pregnancy, the human placenta expresses the gene for CRH (pCRH) resulting in detectable levels in maternal plasma that increases 20- to 40-fold over the course of gestation. Placental CRH is identical to CRH of hypothalamic origin in size, structure, immunoreactivity, and bioactivity. However, unlike the negative feedback between adrenal cortisol and hypothalamic CRH, cortisol stimulates the synthesis and release of pCRH. The bidirectional release of pCRH into maternal and fetal compartments is associated with regulating the timing of delivery, remodeling the fetal nervous system, and influencing developmental trajectories. Fetal exposure to pCRH during early and late gestation is associated with unique patterns of cortical thinning in school-age children. Placental CRH is elevated in response to physical and behavioral stress and may be an integrative marker of early adversity.

Cortical Thinning and Neuropsychiatric Outcomes in Children Exposed to Prenatal Adversity: A Role for Placental CRH?

The authors sought to assess associations among early-life exposure to adversity, the development and maturation of neurons and brain circuits, and neurodevelopmental outcomes. Specifically, they examined whether fetal exposure to placental corticotropin-releasing hormone (CRH), a molecule conveying maternal signals to the fetus, predicts brain growth and neuropsychiatric outcomes in school-age children. In a large, well-characterized prospective cohort, concentrations of placental CRH (pCRH) in maternal plasma were determined during five intervals during gestation. When the children reached school age, their brain structures were examined using MRI, and emotional and cognitive tests assessing internalizing and externalizing behaviors and attention were administered (N=97, 49 of them girls). Levels of pCRH during gestation predicted structural and functional brain outcomes in children. Specifically, fetal exposure to elevated pCRH levels was associated with thinning of selective cortical regions and with commensurate cognitive and emotional deficits. The relations among fetal exposure to pCRH, cortical thinning, and childhood function were sex specific. In view of the established effects of CRH on maturation and arborization of cortical neurons, and the major contribution of dendrites to cortical volume, these findings position pCRH as an important mediator of the consequences of early-life adversity on neuropsychiatric outcomes.

Screening a small molecule library to identify inhibitors of NF-\u03baB inducing kinase and pro-labor genes in human placenta

The non-canonical NF-κB signaling (RelB/p52) pathway drives pro-labor genes in the human placenta, including corticotropin-releasing hormone (CRH) and cyclooxygenase-2 (COX-2), making this a potential therapeutic target to delay onset of labor. Here we sought to identify small molecule compounds from a pre-existing chemical library of orally active drugs that can inhibit this NF-κB signaling, and in turn, human placental CRH and COX-2 production. We used a cell-based assay coupled with a dual-luciferase reporter system to perform an in vitro screening of a small molecule library of 1,120 compounds for inhibition of the non-canonical NF-κB pathway. Cell toxicity studies and drug efflux transport MRP1 assays were used to further characterize the lead compounds. We have found that 14 drugs have selective inhibitory activity against lymphotoxin beta complex-induced activation of RelB/p52 in HEK293T cells, several of which also inhibited expression of CRH and COX-2 in human term trophoblast. We identified sulfapyridine and propranolol with activity against CRH and COX-2 that deserve further study. These drugs could serve as the basis for development of orally active drugs to affect length of gestation, first in an animal model, and then in clinical trials to prevent preterm birth during human pregnancy.

Abnormal dendritic maturation of developing cortical neurons exposed to corticotropin releasing hormone (CRH): Insights into effects of prenatal adversity?

Corticotropin releasing hormone (CRH) produced by the hypothalamus initiates the hypothalamic-pituitary-adrenal (HPA) axis, which regulates the body’s stress response. CRH levels typically are undetectable in human plasma, but during pregnancy the primate placenta synthesizes and releases large amounts of CRH into both maternal and fetal circulations. Notably, placental CRH synthesis increases in response to maternal stress signals. There is evidence that human fetal exposure to high concentrations of placental CRH is associated with behavioral consequences during infancy and into childhood, however the direct effects on of the peptide on the human brain are unknown. In this study, we used a rodent model to test the plausibility that CRH has direct effects on the developing cortex. Because chronic exposure to CRH reduces dendritic branching in hippocampal neurons, we tested the hypothesis that exposure to CRH would provoke impoverishment of dendritic trees in cortical neurons. This might be reflected in humans as cortical thinning. We grew developing cortical neurons in primary cultures in the presence of graded concentrations of CRH. We then employed Sholl analyses to measure dendritic branching and total dendritic length of treated cells. A seven-day exposure to increasing levels of CRH led to a significant, dose-dependent impoverishment of the branching of pyramidal-like cortical neurons. These results are consistent with the hypothesis that, rather than merely being a marker of prenatal stress, CRH directly decreases dendritic branching. Because dendrites comprise a large portion of cortical volume these findings might underlie reduced cortical thickness and could contribute to the behavioral consequences observed in children exposed to high levels of CRH in utero.

In pregnancy increased maternal STAI trait stress score shows decreased insulin sensitivity and increased stress hormones

IntroductionChronic or acute stressors influence maternal and fetal Hypothalamus-Pituitary-Adrenal Axes (HPA) during pregnancy. In this study, the effect of maternal stress into maternal insulin sensitivity was investigated during pregnancy. Materials and methodsEighty-two pregnant women [aged 27.1±2.5 (mean±SD) yrs; BMI=25±2.2kg/m2] had at the 2nd and 3rd trimesters anthropometry, fasting blood samples (cortisol, Corticotropin Releasing Hormone (CRH), active amylin, Interleukin (IL6)), Oral Glucose Tolerance Test (OGTT) for glucose and insulin, state-trait anxiety inventory (STAI) trait and state questionnaires (for stress assessment). ResultsMaternal cortisol, CRH and STAI state score increased significantly from 2nd to 3rd trimester. At these trimesters women with STAI trait scores ≥40 had greater serum cortisol and CRH concentrations and lower insulin sensitivity index (ISI) values than those with scores <40 while STAI trait score predicted negatively ISI. At the 2nd trimester maternal CRH concentrations correlated positively with maternal STAI state, Homeostatic Model Assessment Insulin Resistance (HOMAR), 1st and 2nd phase insulin secretion and negatively with ISI. STAI trait correlated negatively with ISI. STAI state correlated positively with maternal systolic blood pressure and HOMAR. At the 3rd trimester STAI trait correlated negatively and positively with ISI and STAI state, respectively, while STAI state correlated positively with HOMAR. In women with STAI state scores ≥40, these scores correlated positively with maternal CRH. ConclusionsIn normal pregnant women, enhanced long-term stress is associated with decreased insulin sensitivity. Both long- and short- term stress are associated with enhanced maternal HPA axis and increased placental CRH secretion.

The flame retardant 2,2′,4,4′-Tetrabromodiphenyl ether enhances the expression of corticotropin-releasing hormone in the placental cell model JEG-3

Polybrominated diphenyl ethers (PBDEs) are chemicals used as flame retardants in household products. After disposing of these items, PBDEs leach from the products by surface water. BDE-47 is a PBDE congener commonly isolated from contaminated food and is the most studied isomer. The placenta is the major source of hormones during pregnancy, and an elevated level of corticotrophin-releasing hormone (CRH) is associated with premature delivery. In the present study, we examined changes in the placental CRH expression under BDE-47 exposure in the JEG-3 cell model system. These placental cells are derived from human choriocarcinoma. Our result showed that this pollutant induced the CRH mRNA expression at 0.5 nM or above in the cells. A similar trend was observed when CRH peptide was determined by Western analysis in the cell lysates. As previous studies have shown the importance of signal transduction pathways in the gene regulation, the status of some protein kinases in the present study was investigated. The phosphorylated PKCα, JNK, and P38 were increased by the toxicant treatment, and administering the specific inhibitors could counteract the induced CRH expression. It appeared that the signaling transduction pathway of PKC was a significant contributor in the transcriptional regulation. Further study by using Electrophoretic Mobility Shift Assay suggested that AP-2 was the ultimate DNA-binding element for the initiation of gene transcription. Because an untimely increased CRH may compromise fetal development and induce preterm birth, the present study suggested that endocrine changes in pregnancy should be taken into consideration in the next assessment.

Assessing placental corticotrophin-releasing hormone disruption by hexestrol in a cell model.

Studies have shown that corticotrophin-releasing hormone (CRH) and relaxin are associated with early delivery. Our lab previously has shown the mycotoxin zeranol increases placental CRH expression. The mycotoxin is used in the farming industry to promote cattle growth, and some synthetic hormones are also used for the same purposes. In order to complete the picture of these growth promoting agents, we attempted to examine the synthetic hormones on the placental gene expression in the current study. Among the tested compounds, hexestrol induced the CRH mRNA and protein expression at 100nM in JEG-3 cells. As signal transduction pathways have been described in the transcriptional control previously, the activations of several protein kinases were determined. P38, PKCβ and JNK were activated upon hexestrol treatment. Since the P38-inhibitor SB203580 prevented hexestrol from inducing CRH in a subsequent experiment, P38 was likely involved in the transcriptional regulation. Electrophoretic mobility shift assay revealed an increase in the CRE binding activity in CRH promoter. This study showed that hexestrol exposure might be a concern for pregnant women.

Fetal exposure to placental corticotropin-releasing hormone is associated with child self-reported internalizing symptoms

ObjectiveFetal exposure to maternal prenatal stress hormones such as cortisol exerts influences on the developing nervous system that persist and include risk for internalizing symptoms later in life. Placental corticotropin-releasing hormone (pCRH) is a feto-placental stress signal that also shapes fetal neurodevelopment and may be a more direct indicator of the fetal experience than maternal stress hormones. The programming effects of pCRH on child development are unknown. The current investigation examined associations between prenatal maternal and placental stress hormone exposures (maternal cortisol and pCRH) and child self-reported internalizing symptoms at age 5. MethodMaternal plasma cortisol and pCRH levels were measured at 15, 19, 25, 31, and 36 weeks’ gestation in a sample of 83 women and their 91 children (8 sibling pairs from separate pregnancies), who were born full-term. Child self-reported internalizing symptoms at age 5 were obtained using scales of the Berkeley Puppet Interview. ResultsPlacental CRH profiles (including elevations in mid-gestation) were associated with higher levels of internalizing symptoms at age 5. This effect was not explained by critical prenatal or postnatal influences, including obstetric risk, concurrent maternal psychological state, and family socio-economic status. Prenatal maternal cortisol was not significantly associated with child self-reported internalizing symptoms. ConclusionsFindings suggest that elevated exposures to the feto-placental stress signal pCRH exert programming effects on the developing fetal central nervous system, with lasting consequences for child mental health.

Mono-(2-Ethylhexyl) Phthalate Promotes Pro-Labor Gene Expression in the Human Placenta.

Women exposed to phthalates during pregnancy are at increased risk for delivering preterm, but the mechanism behind this relationship is unknown. Placental corticotropin-releasing hormone (CRH) and cyclooxygenase-2 (COX-2) are key mediators of parturition and are regulated by the non-canonical NF-kB (RelB/p52) signaling pathway. In this study, we demonstrate that one of the major phthalate metabolites, mono-(2-ethylhexyl)-phthalate (MEHP), increased CRH and COX-2 mRNA and protein abundance in a dose-dependent manner in primary cultures of cytotrophoblast. This was coupled with an increase in nuclear import of RelB/p52 and its association with the CRH and COX-2 promoters. Silencing of NF-kB inducing kinase, a central signaling component of the non-canonical NF-kB pathway, blocked MEHP-induced upregulation of CRH and COX-2. These results suggest a potential mechanism mediated by RelB/p52 by which phthalates could prematurely induce pro-labor gene activity and lead to preterm birth.

How Can a Mother's Childhood Experiences Be Transmitted to Her Children?

Traumas that were experienced in childhood can influence adults' interactions with their children, but there may be an additional direct effect before the child is born. To determine whether a mother's early experience directly affects the fetus physiologically, investigators correlated placental corticotrophin-releasing hormone (pCRH) and the amount of childhood abuse and neglect reported by 295 pregnant women on a questionnaire. Because most CRH in maternal …