Tipos de partos y niveles de oxitocina, cortisol y hormonas tiroideas en plasma del cordón umbilical / Types of deliveries and levels of oxytocin, cortisol and thyroid hormones in umbilical cord plasma

Introducción: La placenta sintetiza y secreta varias hormonas que permiten la regulación del embarazo, el trabajo de parto y la adaptación metabólica materno-fetal. Su comportamiento asociado al tipo de parto puede dar información relevante sobre efectos epigenéticos. Objetivo: Describir el tipo de parto con los niveles de oxitocina, cortisol y hormonas tiroideas en plasma de cordón umbilical al nacer. Método: A 50 mujeres con embarazos principalmente normales se les cuantificaron los niveles neurohormonales en plasma de cordón umbilical, obtenido inmediatamente tras el periodo expulsivo. Los resultados se incorporaron a la base de datos clínicos de cada participante y se analizaron con Stata v.14.0. El protocolo fue aprobado por el comité de ética. Resultados: Hubo 33 partos vaginales (12 espontáneos, 13 acelerados y 8 inducidos) y 17 cesáreas (7 electivas y 10 de urgencia). Se observaron mayores niveles de cortisol en los partos vaginales acelerados; las cesáreas tuvieron menores niveles de cortisol y hormona estimulante de la tiroides. Las intervenciones clínicas, con altos o bajos niveles hormonales, están en directa relación con el tipo de parto. Conclusiones: El cortisol y la hormona estimulante de la tiroides medidos en plasma de cordón umbilical variaron según el tipo de parto. Esto es una primera cuantificación de hormonas en plasma de cordón umbilical y su posible regulación placentaria a propósito del tipo de parto.

Introduction: The placenta synthesizes and secretes several hormones allowing the regulation of pregnancy, labor and maternal-fetal metabolic adaptation. Their behavior associated with the type of delivery, may provide relevant information on epigenetic effects. Objective: To describe the type of delivery with the levels of oxytocin, cortisol and thyroid hormones in umbilical cord plasma at birth. Method: Neurohormonal levels from umbilical cord plasma obtained immediately post expulsion, were quantified in 50 women with mainly normal pregnancies. Results incorporated into the clinical database of each participant, statistically analyzed in Stata v.14.0. Protocol approved by ethics committee. Results: 33 were vaginal deliveries (12 spontaneous, 13 accelerated, 8 induced) and 17 cesarean sections (7 elective and 10 emergency). Higher cortisol levels were observed in accelerated vaginal deliveries, cesarean sections had lower cortisol and thyroid stimulating hormone levels. While clinical interventions, with high or low hormone levels, were related to the type of delivery. Conclusions: Cortisol and thyroid stimulating hormone measured in umbilical cord plasma varied according to the type of delivery. This is a first quantification of hormones in umbilical cord plasma and their possible placental regulation in relation to the type of delivery.

Evolution of Placental Hormones: Implications for Animal Models.

Human placenta secretes a variety of hormones, some of them in large amounts. Their effects on maternal physiology, including the immune system, are poorly understood. Not one of the protein hormones specific to human placenta occurs outside primates. Instead, laboratory and domesticated species have their own sets of placental hormones. There are nonetheless several examples of convergent evolution. Thus, horse and human have chorionic gonadotrophins with similar functions whilst pregnancy-specific glycoproteins have evolved in primates, rodents, horses, and some bats, perhaps to support invasive placentation. Placental lactogens occur in rodents and ruminants as well as primates though evolved through duplication of different genes and with functions that only partially overlap. There are also placental hormones, such as the pregnancy-associated glycoproteins of ruminants, that have no equivalent in human gestation. This review focusses on the evolution of placental hormones involved in recognition and maintenance of pregnancy, in maternal adaptations to pregnancy and lactation, and in facilitating immune tolerance of the fetal semiallograft. The contention is that knowledge gained from laboratory and domesticated mammals can translate to a better understanding of human placental endocrinology, but only if viewed in an evolutionary context.

Robust Recombinant Expression of Human Placental Ribonuclease Inhibitor in Insect Cells.

Ribonuclease inhibitors (RIs) are an indispensable biotechnological tool for the detection and manipulation of RNA. Nowadays, due to the outbreak of COVID-19, highly sensitive detection of RNA has become more important than ever. Although the recombinant expression of RNase inhibitors is possible in E. coli, the robust expression is complicated by maintaining the redox potential and solubility by various expression tags. In the present paper we describe the expression of RI in baculovirus-infected High Five cells in large scale utilizing a modified transfer vector combining the beneficial properties of Profinity Exact Tag and pONE system. The recombinant RI is expressed at a high level in a fusion form, which is readily cleaved during on-column chromatography. A subsequent anion exchange chromatography was used as a polishing step to yield 12 mg native RI per liter of culture. RI expressed in insect cells shows higher thermal stability than the commercially available RI products (mainly produced in E. coli) based on temperature-dependent RNase inhibition studies. The endotoxin-free RI variant may also be applied in future therapeutics as a safe additive to increase mRNA stability in mRNA-based vaccines.

Unique Aspects of Human Placentation.

Human placentation differs from that of other mammals. A suite of characteristics is shared with haplorrhine primates, including early development of the embryonic membranes and placental hormones such as chorionic gonadotrophin and placental lactogen. A comparable architecture of the intervillous space is found only in Old World monkeys and apes. The routes of trophoblast invasion and the precise role of extravillous trophoblast in uterine artery transformation is similar in chimpanzee and gorilla. Extended parental care is shared with the great apes, and though human babies are rather helpless at birth, they are well developed (precocial) in other respects. Primates and rodents last shared a common ancestor in the Cretaceous period, and their placentation has evolved independently for some 80 million years. This is reflected in many aspects of their placentation. Some apparent resemblances such as interstitial implantation and placental lactogens are the result of convergent evolution. For rodent models such as the mouse, the differences are compounded by short gestations leading to the delivery of poorly developed (altricial) young.

Reactive oxygen species from mitochondria impacts trophoblast fusion and the production of endocrine hormones by syncytiotrophoblasts.

The placenta, a tissue that is metabolically active and rich in mitochondria, forms a critical interface between the mother and developing fetus. Oxidative stress within this tissue, derived from the dysregulation of reactive oxygen species (ROS), has been linked to a number of adverse fetal outcomes. While such outcomes have been associated with mitochondrial dysfunction, the causal role of mitochondrial dysfunction and mitochondrially generated ROS in altering the process of placentation remains unclear. In this study, mitochondrial complex I activity was attenuated using 10 nM rotenone to induce cellular oxidative stress by increasing mitochondrial ROS production in the BeWo choriocarcinoma cell line. Increased mitochondrial ROS resulted in a significant decrease in the transcripts which encode for proteins associated with fusion (GCM1, ERVW-1, and ERVFRD-1) resulting in a 5-fold decrease in the percentage of BeWo fusion. This outcome was associated with increased indicators of mitochondrial fragmentation, as determined by decreased expression of MFN2 and OPA1 along with an increase in a marker of mitochondrial fission (DRP1). Importantly, increased mitochondrial ROS also resulted in a 5.0-fold reduction of human placental lactogen (PL) and a 4.4-fold reduction of insulin like growth factor 2 (IGF2) transcripts; hormones which play an important role in regulating fetal growth. The pre-treatment of rotenone-exposed cells with 5 mM N-acetyl cysteine (NAC) resulted in the prevention of these ROS mediated changes in BeWo function and supports a central role for mitochondrial ROS signaling in the maintenance and function of the materno-fetal interface.

Expression Analysis, Functional Marker Development and Verification of AgFNSI in Celery.

Apigenin is one of the primary flavonoids in celery, which has a high medicinal value. Flavone synthase I (FNSI) is the last step enzyme in apigenin biosynthesis. In this study, the 1492 bp promoter sequence before AgFNSI initiation codon (ATG) of celery was obtained, which included methyl jasmonate (MeJA) responsive elements, light responsive elements, anaerobic induction elements and five MYB binding sites. AgFNSI was sensitive to temperature, UV-B, water deficit and MeJA. Comparative analysis of AgFNSI genome and promoter sequences among celery accessions with different apigenin content showed that there were four allelic variations in AgFNSI, and four accessions with high apigenin content belonged to AgFNSIa, and five accessions with low apigenin content belonged to AgFNSIc. Three pairs of dominant complementary markers were designed based on the single-nucleotile polymorphisms (SNPs) of the AgFNSIa and AgFNSIc genomes and promoter sequences. Three pairs of functional markers were validated by 112 celery accessions. The results showed that AFPA1/AFPB1 detected significant differences in apigenin content between different genotypes. Therefore, marker AFPA1/AFPB1 is associated with apigenin content in celery and could be used for the genetic improvement of apigenin content in celery.

Determinants of Maternal Insulin Resistance during Pregnancy: An Updated Overview.

Insulin resistance changes over time during pregnancy, and in the last half of the pregnancy, insulin resistance increases considerably and can become severe, especially in women with gestational diabetes and type 2 diabetes. Numerous factors such as placental hormones, obesity, inactivity, an unhealthy diet, and genetic and epigenetic contributions influence insulin resistance in pregnancy, but the causal mechanisms are complex and still not completely elucidated. In this review, we strive to give an overview of the many components that have been ascribed to contribute to the insulin resistance in pregnancy. Knowledge about the causes and consequences of insulin resistance is of extreme importance in order to establish the best possible treatment during pregnancy as severe insulin resistance can result in metabolic dysfunction in both mother and offspring on a short as well as long-term basis.

Receptor expression by JEG-3 trophoblast cells in the presence of placenta secreted factors.

Preeclampsia still remains one of the most severe pregnancy complications and is an actual problem in the obstetrics practice. At present, the joint impact of cytokines and other placenta secreted factors on trophoblast cell functional activity during preeclampsia complicated pregnancy remains unclear. The aim of the study is to estimate the surface receptors expression by trophoblast cells in the presence of placenta secreted factors during physiological pregnancy and at preeclampsia. Trophoblast cells of the JEG-3 line were incubated in the presence of supernatants obtained by cultivation of placentas from women with physiological pregnancy and with preeclampsia. Surface receptors expression by trophoblast cells was estimated by FACS Canto II flow cytometer. It was established that in the third trimester both under normal and pathological conditions, the placenta secreted factors impact on the cytokine receptor expression by trophoblast differs while the trophoblast response capacity to the migration and proliferation stimulating and inhibiting signals remains stable. JEG-3 line cells enhanced the expression of CD186, CD140a, Integrin ß6, VE-cadherin, CD29, and CD140a in the case of incubation in the presence of placenta supernatants from the third-trimester pregnancy complicated with preeclampsia compared to incubation in the presence of placenta supernatants form the third trimester of physiological pregnancy.

Chromosomal architecture and placental expression of the human growth hormone gene family are targeted by pre-pregnancy maternal obesity.

The human (h) placental lactogenic hormone chorionic somatomammotropin (CS) is highly produced during pregnancy and acts as a metabolic adaptor in response to maternal insulin resistance. Maternal obesity can exacerbate this "resistance", and a >75% decrease in CS RNA levels was observed in term placentas from obese vs. lean women. The genes coding for hCS ( hCS-A and hCS-B) and placental growth hormone ( hGH-V) as well as the hCS-L pseudogene and pituitary growth hormone (GH) gene ( hGH-N) are located at a single locus on chromosome 17. Three remote hypersensitive sites (HS III-V) located >28 kb upstream of hGH-N as well as local hCS gene promoter and enhancer regions are implicated in hCS gene expression. A placenta-specific chromosomal architecture, including interaction between HS III-V and hCS but not hGH gene promoters, was detected in placentas from lean women (BMI <25 kg/m2) by using the chromosome conformation capture assay. This architecture was disrupted by pre-pregnancy maternal obesity (BMI >35 kg/m2), resulting in a predominant interaction between HS III and the hGH-N promoter, which was also observed in nonplacental tissues. This was accompanied by a decrease in hCS levels, which was consistent with reduced RNA polymerase II and CCAAT/enhancer-binding protein-ß association with individual hCS promoter and enhancer sequences, respectively. Thus, pre-pregnancy maternal obesity disrupts the placental hGH/CS gene locus chromosomal architecture. However, based on data from obese women who develop GDM, insulin treatment partially recapitulates the chromosomal architecture seen in lean women and positively affects hCS production, presumably facilitating prolactin receptor-related signaling by hCS.

Human Placental Growth Hormone Variant in Pathological Pregnancies.

Growth hormone (GH), an endocrine hormone, primarily secreted from the anterior pituitary, stimulates growth, cell reproduction, and regeneration and is a major regulator of postnatal growth. Humans have two GH genes that encode two versions of GH proteins: a pituitary version (GH-N/GH1) and a placental GH-variant (GH-V/GH2), which are expressed in the syncytiotrophoblast and extravillous trophoblast cells of the placenta. During pregnancy, GH-V replaces GH-N in the maternal circulation at mid-late gestation as the major circulating form of GH. This remarkable change in spatial and temporal GH secretion patterns is proposed to play a role in mediating maternal adaptations to pregnancy. GH-V is associated with fetal growth, and its circulating concentrations have been investigated across a range of pregnancy complications. However, progress in this area has been hindered by a lack of readily accessible and reliable assays for measurement of GH-V. This review will discuss the potential roles of GH-V in normal and pathological pregnancies and will touch on the assays used to quantify this hormone.

HBxAg suppresses cell apoptosis and promotes the secretion of placental hormones in human placental trophoblasts via activation of the EGFR/Akt pathway.

The aim of this study is to investigate the role of Hepatitis B virus x (HBx) in the growth and secretion of human placental trophoblasts. Firstly, placenta tissues were collected from pregnant HBV carriers with various viral loads. The results of immunohistochemical technique showed that the HBx protein and pEGFR protein levels were both markedly increased with the viral load elevation. Then, a placental trophoblast cell strain (JEG-3-HBx), which stably expressed HBx mRNA and protein, was established with the pcDNA-HBx transfection followed by the G418 selection. The JEG-3-HBx strain displayed distinct activation of the EGFR/AKT pathway, a lower level of cell apoptosis, and higher secretion levels of placental hormones, including human chorionic gonadotropin (hCG), progesterone, estrogen and ß-endorphin. Subsequently, HBx siRNA was used to silence the HBx gene in the JEG-3-HBx strain. Our data showed that the HBx siRNA transfection markedly suppressed the activation of the EGFR/AKT pathway, promoted cell apoptosis, and reduced the secretion of the placental hormones. Finally, EGF was applied to simulate the JEG-3-HBx strain with or without the HBx siRNA transfection. EGF treatment counteracted the reduction of cell apoptosis and the suppression of hormone secretion caused by HBx siRNA in the cell strain. In conclusion, the pEGFR protein was robustly upregulated in HBx-infected human placenta tissues and trophoblast cells. HBx reduces cell apoptosis and promotes the secretion of placental hormones in human placental trophoblast cells via activation of the EGFR/Akt pathway.

Maternal Sleep-Disordered Breathing.

Emerging literature suggests that sleep-disordered breathing (SDB) worsens over the course of pregnancy and is associated with adverse maternal and fetal outcomes. Earlier studies, using mainly snoring as a surrogate marker for SDB, have shown an increase in the prevalence of SDB during pregnancy compared with that in the pregravid state. More recently, prospective observational studies in which the investigators ascertained SDB by using complete polysomnography have shown a prevalence ranging from approximately 17% to 45% in the third trimester. Pregnancy itself can be associated with daytime hypersomnolence, so complaints of increasing fatigue and sleepiness during pregnancy are not specific for SDB. Moreover, snoring in isolation also has relatively poor sensitivity and specificity as a screening tool for diagnosing maternal SDB. The indications for screening for SDB during routine obstetric prenatal visits are still unclear, but observational studies indicate that maternal SDB is linked with the development of adverse pregnancy outcomes, such as gestational hypertension and gestational diabetes mellitus. Some studies also have identified a relationship between maternal SDB and the delivery of infants who are small for gestational age. Aside from a few small interventional studies of CPAP in pregnant patients with gestational hypertension, little currently is known about whether treatment of SDB during pregnancy improves clinical outcomes for the mother and/or baby. Additional current knowledge gaps include elucidating underlying mechanisms of maternal SDB, determining optimal treatment strategies, and understanding the trajectory of SDB after delivery.

Disorders in barrier protein mRNA expression and placenta secretory activity under the influence of polychlorinated biphenyls in vitro.

Pregnancy disorders are often correlated with the presence of organic pollutants in the tissues of living bodies. The aim of this study was to investigate the effects (over 24 and 48 hours) of polychlorinated biphenyls (PCBs) 153, 126, and 77 at doses of 1, 10, and 100 ng/mL on barrier function and secretory activity in cow placentome sections collected during the second trimester of pregnancy. None of the PCBs affected the viability of the sections (P > 0.05). Polychlorinated biphenyl 153 decreased (P < 0.05) connexin 26 (Cx 26) mRNA expression, and all three PCBs reduced (P < 0.05) Cx 43 mRNA expression. Cx 32 mRNA expression showed a downward trend (P > 0.05) under the influence of PCBs 126 and 77. Moreover, PCBs 153 and 126 increased keratin 8 (KRT8) mRNA expression, whereas all PCBs decreased (P < 0.05) placenta specific protein 1 (PLAC-1) mRNA expression without changing (P > 0.05) hypoxia inducible factor 1α (HIF1α) mRNA expression. Concomitantly, PCBs 153 and 126 stimulated (P < 0.05) cyclooxygenase 2 (COX-2) mRNA expression, all PCBs increased (P < 0.05) prostaglandin E2 synthase (PGES) mRNA expression, and PCBs 126 and 77 increased prostaglandin E2 (PGE2) secretion. All three PCBs decreased (P < 0.05) prostaglandin F2α synthase (PGFS) mRNA expression and prostaglandin F2α (PGF2α) secretion. In addition, all three PCBs increased (P < 0.05) neurophysin I/oxytocin (NP-I/OT) mRNA expression and OT secretion but did not affect peptidyl-glycine-α-amidating monooxygenase (PGA) mRNA expression (P > 0.05). Moreover, the PCBs increased (P < 0.05) estradiol (E2) secretion, whereas progesterone (P4) secretion remained unchanged (P > 0.05). These changes could affect trophoblast invasion and uterine contractility and thus impact the course of gestation and/or fetal development in the cow.

Changes in the mRNA expression of structural proteins, hormone synthesis and secretion from bovine placentome sections after DDT and DDE treatment.

Disorders in the barrier function and secretory activity of the placenta can be caused by xenobiotics (XB) present in the environment and their accumulation in tissues of living organisms. Thus, the aim of this study was to investigate the effect of 1,1,1-trichloro-2,2,-bis-4-chlorophenyl-ethane (DDT) and its metabolite 1,1-dichloro-2,2-bis-4-chlorophenyl-ethene (DDE) (for 24 or 48h) at doses of 1, 10 or 100ng/ml on the function of cow placentome sections in the second trimester of pregnancy. DDT and DDE affected neither (P>0.05) the viability nor hypoxia inducible factor 1 (HIF1α) mRNA expression of the sections. XB decreased (P<0.05) connexin (Cx) 26, 32, 43 and placenta-specific 1 (PLAC-1) mRNA expression but did not affect (P>0.05) keratin 8 (KRT8) mRNA expression. DDT and DDE also reduced (P<0.05) prostaglandin F2α (PGF2α) synthase (PGFS) mRNA expression, while DDT increased (P<0.05) prostaglandin E2 (PGE2) synthase (PGES) mRNA expression. Neither cyclooxygenase 2 (COX-2) mRNA expression nor PGF2α and PGE2 secretion were affected. Both DDT and DDE increased (P<0.05) neurophysin I/oxytocin (NP1/OT) mRNA expression and oxytocin (OT), oestradiol (E2) and progesterone (P4) secretion while DDT stimulated only 3ß-hydroxysteroid dehydrogenase (3ßHSD) and cholesterol side-chain cleavage enzyme (CYP11A1) mRNA expression (P<0.05). In summary, DDT and DDE impaired the barrier function and secretory activity of the placenta. Thus, these compounds can disrupt trophoblast invasion, myometrium contractility and gas/nutrient exchange throughout pregnancy in cows.

Hypoxia-induced responses by endothelial colony-forming cells are modulated by placental growth factor.

BACKGROUND: Endothelial colony-forming cells (ECFCs), also termed late outgrowth endothelial cells, are a well-defined circulating endothelial progenitor cell type with an established role in vascular repair. ECFCs have clear potential for cell therapy to treat ischaemic disease, although the precise mechanism(s) underlying their response to hypoxia remains ill-defined. METHODS: In this study, we isolated ECFCs from umbilical cord blood and cultured them on collagen. We defined the response of ECFCs to 1% O2 exposure at acute and chronic time points. RESULTS: In response to low oxygen, changes in ECFC cell shape, proliferation, size and cytoskeleton phenotype were detected. An increase in the number of senescent ECFCs also occurred as a result of long-term culture in 1% O2. Low oxygen exposure altered ECFC migration and tube formation in Matrigel®. Increases in angiogenic factors secreted from ECFCs exposed to hypoxia were also detected, in particular, after treatment with placental growth factor (PlGF). Exposure of cells to agents that stabilise hypoxia-inducible factors such as dimethyloxalylglycine (DMOG) also increased PlGF levels. Conditioned medium from both hypoxia-treated and DMOG-treated cells inhibited ECFC tube formation. This effect was reversed by the addition of PlGF neutralising antibody to the conditioned medium, confirming the direct role of PlGF in this effect. CONCLUSIONS: This study deepens our understanding of the response of ECFCs to hypoxia and also identifies a novel and important role for PlGF in regulating the vasculogenic potential of ECFCs.

Chronic Protein Restriction in Mice Impacts Placental Function and Maternal Body Weight before Fetal Growth.

Mechanisms of resource allocation are essential for maternal and fetal survival, particularly when the availability of nutrients is limited. We investigated the responses of feto-placental development to maternal chronic protein malnutrition to test the hypothesis that maternal low protein diet produces differential growth restriction of placental and fetal tissues, and adaptive changes in the placenta that may mitigate impacts on fetal growth. C57BL/6J female mice were fed either a low-protein diet (6% protein) or control isocaloric diet (20% protein). On embryonic days E10.5, 17.5 and 18.5 tissue samples were prepared for morphometric, histological and quantitative RT-PCR analyses, which included markers of trophoblast cell subtypes. Potential endocrine adaptations were assessed by the expression of Prolactin-related hormone genes. In the low protein group, placenta weight was significantly lower at E10.5, followed by reduction of maternal weight at E17.5, while the fetuses became significantly lighter no earlier than at E18.5. Fetal head at E18.5 in the low protein group, though smaller than controls, was larger than expected for body size. The relative size and shape of the cranial vault and the flexion of the cranial base was affected by E17.5 and more severely by E18.5. The junctional zone, a placenta layer rich in endocrine and energy storing glycogen cells, was smaller in low protein placentas as well as the expression of Pcdh12, a marker of glycogen trophoblast cells. Placental hormone gene Prl3a1 was altered in response to low protein diet: expression was elevated at E17.5 when fetuses were still growing normally, but dropped sharply by E18.5 in parallel with the slowing of fetal growth. This model suggests that nutrients are preferentially allocated to sustain fetal and brain growth and suggests the placenta as a nutrient sensor in early gestation with a role in mitigating impacts of poor maternal nutrition on fetal growth.

A nuclear-directed human pancreatic ribonuclease (PE5) targets the metabolic phenotype of cancer cells.

Ribonucleases represent a new class of antitumor RNA-damaging drugs. However, many wild-type members of the vertebrate secreted ribonuclease family are not cytotoxic because they are not able to evade the cytosolic ribonuclease inhibitor. We previously engineered the human pancreatic ribonuclease to direct it to the cell nucleus where the inhibitor is not present. The best characterized variant is PE5 that kills cancer cells through apoptosis mediated by the p21(WAF1/CIP1) induction and the inactivation of JNK. Here, we have used microarray-derived transcriptional profiling to identify PE5 regulated genes on the NCI/ADR-RES ovarian cancer cell line. RT-qPCR analyses have confirmed the expression microarray findings. The results show that PE5 cause pleiotropic effects. Among them, it is remarkable the down-regulation of multiple genes that code for enzymes involved in deregulated metabolic pathways in cancer cells.

Lower levels of placental growth hormone in early pregnancy in women with type 1 diabetes and large for gestational age infants.

OBJECTIVE: To evaluate whether levels of placental growth hormone (GH) and Insulin-like Growth Factor-I (IGF-I) are associated with development of LGA infants in pregnant women with type 1 diabetes. DESIGN: Observational study of 103 consecutive pregnant women with long-term type 1 diabetes and median HbA1c 6.6% (range 4.9-10.5) (49 mmol/mol (30-91)) in early pregnancy. At 8, 14, 21, 27 and 33 weeks weight was recorded and blood was sampled for measurements of placental GH, IGF-I and HbA1c. LGA was defined as birth weight >90th percentile after adjustment for gender and gestational age. RESULTS: Throughout pregnancy placental GH levels were similar in 51 (50%) women delivering LGA infants compared with the remaining women except at 8 weeks where placental GH levels were lower in women with LGA infants (1.1 ng/ml (0.1-4.3) vs. 1.7 (0.3-11.7), p = 0.04). IGF-I levels were similar in women with and without LGA infants (p=0.97). Gestational age at first blood sampling was similar in women with and without LGA infants (60 days (37-89) vs. 61.5 (42-94), p = 0.42). Placental GH levels at 14 weeks correlated negatively with weight gain in early pregnancy (r=-0.32, p=0.002). As predictors of LGA infants,multivariate logistic regression analysis identified placental GH levels at 8 weeks (OR 0.4 (95% CI: 0.2-0.9), p = 0.02), HbA1c at 33 weeks (3.6 (1.3-9.9), p = 0.01) and parity ≥1 (3.1 (1.3-7.5), p = 0.01) after adjustment for pre-pregnancy BMI. CONCLUSIONS: Women delivering LGA infants had lower placental GH levels in early pregnancy. Growth factors and maternal weight gain in early pregnancy may be important for healthy fetal growth.

Formaldehyde Crosses the Human Placenta and Affects Human Trophoblast Differentiation and Hormonal Functions.

The chorionic villus of the human placenta is the source of specific endocrine functions and nutrient exchanges. These activities are ensured by the syncytiotrophobast (ST), which bathes in maternal blood. The ST arises and regenerates throughout pregnancy by fusion of underlying cytotrophoblasts (CT). Any anomaly of ST formation or regeneration can affect pregnancy outcome and fetal growth. Because of its direct interaction with maternal blood, the ST is sensitive to drugs, pollutants and xenohormones. Ex vivo assays of perfused cotyledon show that formaldehyde, a common pollutant present in furniture, paint and plastics, can accumulate in the human placenta and cross to the fetal compartment. By means of RT-qPCR, immunoblot and immunocytochemistry experiments, we demonstrate in vitro that formaldehyde exerts endocrine toxicity on human trophoblasts, including a decrease in the production of protein hormones of pregnancy. In addition, formaldehyde exposure triggered human trophoblast fusion by upregulating syncitin-1 receptor expression (ASC-type amino-acid transporter 2: ASCT2). Moreover, we show that formaldehyde-exposed trophoblasts present an altered redox status associated with oxidative stress, and an increase in ASCT2 expression intended to compensate for this stress. Finally, we demonstrate that the adverse effects of formaldehyde on trophoblast differentiation and fusion are reversed by N-acetyl-L-cysteine (Nac), an antioxidant.

Comparative Immunohistochemistry of Placental Corticotropin-Releasing Hormone and the Transcription Factor RelB-NFκB2 Between Humans and Nonhuman Primates.

The transcription factor RelB-NFκB2, activated by the noncanonical NFκB pathway, positively regulates corticotropin-releasing hormone (CRH) and prostaglandin production in the term human placenta and may play an important role in the timing of human parturition. Here we explored whether RelB-NFκB2 signaling plays a role in parturition in nonhuman anthropoid primates. We performed immunohistochemical staining to assess the correlation between CRH and nuclear activity of RelB-NFκB2 heterodimers in term placentas from humans, 3 catarrhine primate species, and a single platyrrhine primate species. Consistent with our previous studies, the human placenta showed cytoplasmic staining for CRH and nuclear staining for RelB-NFκB2. Similar staining patterns were noted in the 3 catarrhine primates (chimpanzee, baboon, and rhesus macaque). The platyrrhine (marmoset) placentas stained positively for CRH and RelB but not for NFκB2. Catarrhine (but not platyrrhine) nonhuman primate term placentas demonstrate the same CRH staining and nuclear localization patterns of RelB and NFκB2 as does human placenta. These results suggest that catarrhine primates, particularly rhesus macaques, may serve as useful animal models to study the biologic significance of the noncanonical NFκB pathway in human pregnancy.