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STUDY QUESTION: Is the cardiometabolic health of adolescents conceived through ART worse than that of their counterparts conceived without ART? SUMMARY ANSWER: The majority of cardiometabolic and vascular health parameters of adolescents conceived through ART are similar or more favourable, than those of their counterparts of similar age and conceived without ART. WHAT IS KNOWN ALREADY: It has been proposed that the cardiometabolic health of offspring conceived with ART may be unfavourable compared to that of their counterparts conceived without ART. The literature pertaining to cardiometabolic health of offspring conceived after ART is contradictory, but generally suggests unfavourable cardiometabolic health parameters, such as an increase in blood pressure (BP), vascular dysfunction and adiposity, as well as unfavourable glucose and lipid profiles. With over 8 million children and adults born through ART worldwide, it is important to investigate whether these early signs of adverse cardiometabolic differences persist into adolescence and beyond. STUDY DESIGN, SIZE, DURATION: The Growing Up Healthy Study (GUHS) is a prospective cohort study that recruited 303 adolescents and young adults conceived after ART (aged 13-21 years) and born between 1991 and 2001 in Western Australia. Their health parameters, including cardiometabolic factors, were assessed and compared with counterparts from the Raine Study Generation 2 (Gen2). The 2868 Gen2 participants were born 1989-1992 and are representative of the Western Australian adolescent population. At ∼17 years of age (2013-2017), 163 GUHS participants replicated assessments previously completed by Gen2 at a similar age. PARTICIPANTS/MATERIALS, SETTING, METHODS: Cardiometabolic parameters were compared between a total of 163 GUHS and 1457 Gen2 adolescents. Separate male (GUHS n = 81, Gen2 n = 735) and female (GUHS n = 82, Gen2 n = 722) analyses were conducted. Assessments consisted of a detailed questionnaire including healt

STUDY QUESTION: Are there differences in thyroid function between adolescents and young adults conceived with and without ART? SUMMARY ANSWER: This study demonstrated no evidence of clinically relevant differences in thyroid function between adolescents and young adults conceived with and without ART. WHAT IS KNOWN ALREADY: Studies to date have reported an increase in subclinical hypothyroidism in offspring conceived after ART. It has been suggested that the increase in maternal estrogen (E2) after fresh embryo transfers could affect thyroid function of the offspring. Suboptimal thyroid function at a young age can cause irreversible damage to the central nervous system, which makes early detection and correct treatment essential. STUDY DESIGN, SIZE, DURATION: The Growing Up Healthy Study (GUHS) is a prospective cohort study, which aimed to recruit all adolescents born after conception with ART between 1991 and 2001 in the study area. The included participants (n = 303, aged 13-20 years) completed various health assessments. Depending on the age at enrolment, participants completed thyroid assessments at the 14-or 20-year follow-up. The outcomes of these replicated thyroid assessments were compared to those of participants conceived without ART from the Raine Study Generation 2 (Gen2). The Gen2 participants (n = 2868) were born between 1989 and 1992 and have been recognized to be representative of the local population. PARTICIPANTS/MATERIALS, SETTING, METHODS: Thyroid function assessments were compared between n = 134 GUHS and n = 1359 Gen2 adolescents at age 14 years and between n = 47 GUHS and n = 914 Gen2 young adults at age 20 years. The following mean thyroid hormone concentrations were compared between the cohorts: Thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4) and thyroid peroxidase antibodies (TPOAb). The prevalence of the following thyroid hormone profiles, based on individual thyroid hormone concentrations, was compared

Background Intraamniotic inflammation is associated with up to 40% of preterm births, most notably in deliveries occurring prior to 32 weeks’ gestation. Despite this, there are few treatment options allowing the prevention of preterm birth and associated fetal injury. Recent studies have shown that the small, non-competitive allosteric interleukin (IL)-1 receptor inhibitor, rytvela, may be of use in resolving inflammation associated with preterm birth (PTB) and fetal injury. We aimed to use an extremely preterm sheep model of chorioamnionitis to investigate the anti-inflammatory efficacy of rytvela in response to established intra-amniotic (IA) lipopolysaccharide (LPS) exposure. We hypothesized that rytvela would reduce LPS-induced IA inflammation in amniotic fluid (AF) and fetal tissues. Methods Sheep with a single fetus at 95 days gestation (estimated fetal weight 1.0 kg) had surgery to place fetal jugular and IA catheters. Animals were recovered for 48 hours before being randomized to either: i) IA administration of 2 ml saline 24 hours before 2 ml IA and 2 ml fetal intravenous (IV) administration of saline (Saline Group, n = 7); ii) IA administration of 10 mg LPS in 2 ml saline 24 hours before 2 ml IA and 2 ml fetal IV saline (LPS Group, n = 10); 3) IA administration of 10 mg LPS in 2 ml saline 24 hours before 0.3 mg/fetal kg IA and 1 mg/fetal kg fetal IV rytvela in 2 ml saline, respectively (LPS + rytvela Group, n = 7). Serial AF samples were collected for 120 h. Inflammatory responses were characterized by quantitative polymerase chain reaction (qPCR), histology, fluorescent immunohistochemistry, enzyme-linked inmmunosorbent assay (ELISA), fluorescent western blotting and blood chemistry analysis. Results LPS-treated animals had endotoxin and AF monocyte chemoattractant protein (MCP)-1 concentrations that were significantly higher at 24 hours (immediately prior to rytvela administration) relative to values from Saline Group animals. Following rytvela administr

Oxytocin has been a hormone of interest in understanding both depression and parenting. Here, the role of oxytocin has been explored in understanding the interaction between perinatal depression, history of trauma and subsequent longer-term child socio-emotional outcomes. Data were obtained from 203 pregnant women from the Mercy Pregnancy and Emotional Wellbeing Study (MPEWS), a pregnancy cohort study with data collected across pregnancy, postpartum and until 4 years for mother and child. Maternal antenatal depression was measured using the Structured Clinical Interview for DSM-IV (SCID-IV) together with the Childhood Trauma Questionnaire to measure maternal trauma history. Maternal oxytocin levels were measured by enzyme immunoassay following extraction at four time points across pregnancy and the postpartum. The offspring consisted of 203 children followed up from birth until 4 years of age when they were assessed for DSM 5 depression and anxiety disorders (emotional disorders) using the Preschool Age Psychiatric Assessment. Maternal oxytocin levels increased over pregnancy and the postpartum in both control and depressed women with no difference between groups. Maternal childhood trauma and antenatal antidepressant use was also not associated with maternal oxytocin levels. Lower gestational age, maternal depression and early childhood trauma, and late pregnancy oxytocin concentrations were associated with later childhood emotional disorders; together they predicted 10% of variance for emotional disorders. Oxytocin is a hormone whose role in understanding intergenerational risk from pregnancy to child emotional disorders is dependent on relational context. Future research can expand on understanding these important early predictors of childhood mental health.

© 2017 Bisphenol A (BPA) is a ubiquitous chemical suspected to possess oestrogenic hormonal activities. Male population studies suggest a negative impact on testicular function. As Sertoli cell proliferation occurs during fetal or early postnatal life, it is speculated that oestrogenic environmental exposures may influence mature testicular function. Among 705 Western Australian Pregnancy Cohort (Raine) Study men aged 20–22 years, 404 underwent testicular ultrasound examination (149 had maternal serum available), and/or 365 provided semen (136 had maternal serum) and/or 609 serum samples for sex steroids, gonadotrophins and inhibin B analysis (244 had maternal serum). Maternal serum collected at 18 and 34 weeks' gestation was pooled and assayed for concentrations of total BPA (free plus conjugated) as an estimate of antenatal exposure. Testicular volume was calculated by ultrasonography, and semen analysis performed. Serum LH, FSH and inhibin B were measured by immunoassay; testosterone, oestradiol, oestrone andBPA were measured by liquid chromatography-mass spectrometry. BPA levels were detectable in most (89%) maternal serum samples. After adjustment for maternal smoking, abstinence and varicocele, sperm concentration and motility were significantly correlated to maternal serum BPA (r = 0.18; P = 0.04 for both). No other associations of maternal serum BPA with testicular function were observed.

Gold nanorods are one of the most widely explored inorganic materials in nanomedicine for diagnostics, therapeutics and sensing1. It has been shown that gold nanorods are not cytotoxic and localize within cytoplasmic vesicles following endocytosis, with no nuclear localization2,3, but other studies have reported alterations in gene expression profiles in cells following exposure to gold nanorods, via unknown mechanisms4. In this work we describe a pathway that can contribute to this phenomenon. By mapping the intracellular chemical speciation process of gold nanorods, we show that the commonly used Au–thiol conjugation, which is important for maintaining the noble (inert) properties of gold nanostructures, is altered following endocytosis, resulting in the formation of Au(i)–thiolates that localize in the nucleus5. Furthermore, we show that nuclear localization of the gold species perturbs the dynamic microenvironment within the nucleus and triggers alteration of gene expression in human cells. We demonstrate this using quantitative visualization of ubiquitous DNA G-quadruplex structures, which are sensitive to ionic imbalances, as an indicator of the formation of structural alterations in genomic DNA.

© Wolters Kluwer Health, Inc. All rights reserved. Background Psychotropic medication use in pregnancy has been associated with altered fetal growth. The aim of this study was to investigate the relationship between placental weight and placental weight-to-birth weight (PBW) ratio, as a potential marker of placental efficiency, and medication use in a cohort of women with severe mental illness in pregnancy. Methods A retrospective database analysis was carried out on a cohort of pregnant women with severe mental illness (242 singleton pregnancies) and grouped according to their psychotropic medication use. Demographic, obstetric, neonatal, and psychiatric variables were analyzed using t tests, ?2, analysis of variance, univariate, binary, and multiple regression adjusting for potential confounders. Results Multiple regression analysis demonstrated a mean adjusted increase in placental weight of 114 g (95% confidence interval [CI], 60.2-165.6 g) in women taking antidepressant medication and 113 g (CI, 65.1-162.8 g) in women taking combined antidepressant and atypical antipsychotic medication in pregnancy. There was also a significantly elevated PBW ratio in these 2 medication groups (B 0.02: CI, 0.006-0.034; and B 0.025: CI, 0.012-0.038). Binary regression, adjusted for sex and gestational age, showed a significant odds ratio of 4.57 (95% CI, 2.17-9.62) for PBW ratio of greater than 90% in those taking antidepressant medication, either alone or in combination, compared with unmedicated women. Conclusions The use of antidepressant medication, alone or in combination, has a significant effect on placental weight and PBW ratio after adjusting for confounding variables. Given that this may reflect adverse effects on intrauterine growth and have possible long-term implications for the fetus, further research is warranted to confirm these findings.

Workshops are an important part of the IFPA annual meeting, as they allow for discussion of specialized topics. At the IFPA meeting 2015 there were twelve themed workshops, three of which are summarized in this report. These workshops were related to various aspects of placental biology but collectively covered areas of pregnancy pathologies and placental metabolism: 1) nanomedicine applications and exosome biology; 2) xenobiotics and endocrine disruptors and pregnancy; 3) lipid mediators and placental function.

Background: Ratio of second digit length to fourth digit length (2D:4D) has been extensively used in human and experimental research as a marker of fetal sex steroid exposure. However, very few human studies have measured the direct relationship between fetal androgen or estrogen concentrations and digit ratio. Aims: We investigated the relationships between both androgen and estrogen concentrations in umbilical cord blood and digit ratio in young adulthood. In addition we calculated measures of total serum androgen and total estrogen bioactivity and investigated their relationship to digit ratio. Study design: Prospective cohort study. Subjects: An unselected subset of the Western Australian Pregnancy Cohort (Raine) Study (159 female; 182 male). Outcome measures: Cord serum samples were collected immediately after delivery. Samples were assayed for androgen (testosterone, Δ4-androstenedione, dehydroepiandrosterone) and estrogen (estrone, estradiol, estriol, estetrol) concentrations using liquid-chromatography mass-spectrometry. Digit ratio measurements were taken from hand photocopies at age 19–22 years. Results: For both males and females, there were no significant correlations between digit ratio and any androgen or estrogen concentrations considered individually, the testosterone to estradiol ratio, total androgen bioactivity measure or ratio of androgen to estrogen bioactivity (all p > .05). In males, but not females, total estrogen bioactivity was negatively correlated with left hand digit ratio (r = − .172, p = .02), but this relationship was no longer significant when adjusted for variables known to affect sex steroid concentrations in cord blood. Conclusions: Our findings indicate that digit ratio is not related to fetal androgens or estrogens at late gestation.

© 2015 The Author(s) Published by the Royal Society. All rights reserved. Prenatal testosterone may have a powerful masculinizing effect on postnatal physical characteristics. However, no study has directly tested this hypothesis. Here, we report a 20-year follow-up study that measured testosterone concentrations from the umbilical cord blood of 97 male and 86 female newborns, and procured three-dimensional facial images on these participants in adulthood (range: 21-24 years). Twenty-three Euclidean and geodesic distances were measured from the facial images and an algorithm identified a set of six distances that most effectively distinguished adult males from females. From these distances, a 'gender score' was calculated for each face, indicating the degree of masculinity or femininity. Higher cord testosterone levels were associated with masculinized facial features when males and females were analysed together (n = 183; r = —0.59), as well as when males (n = 86; r = —0.55) and females (n = 97; r = —0.48) were examined separately (p-values < 0.001). The relationships remained significant and substantial after adjusting for potentially confounding variables. Adult circulating testosterone concentrations were available for males but showed no statistically significant relationship with gendered facial morphology (n = 85, r = 0.01, p = 0.93). This study provides the first direct evidence of a link between prenatal testosterone exposure and human facial structure.

The integration of a complex network of signalling molecules promotes implantation of the blastocyst and development of the placenta. These processes are crucial for a successful pregnancy and fetal growth and development. The signalling network involves both cell–cell and cell–extracellular matrix communication. The family of secreted glycoprotein ligands, the Wnts, plays a major role in regulating a wide range of biological processes, including embryonic development, cell fate, proliferation, migration, stem cell maintenance, tumour suppression, oncogenesis and tissue homeostasis. Recent studies have provided evidence that Wnt signalling pathways play an important role in reproductive tissues and in early pregnancy events. The focus of this review is to summarise our present knowledge of expression, regulation and function of the Wnt signalling pathways in early pregnancy events of human and other model systems, and its association with pathological conditions. Despite our recent progress, much remains to be learned about Wnt signalling in human reproduction. The advancement of knowledge in this area has applications in the reduction of infertility and the incidence and morbidity of gestational diseases.

Wnt signalling has important roles in decidualisation, implantation and placentation. We investigated the role of decidua-trophoblast communication and Wnt signalling in the placenta using a co-culture model. Expression of a wide range of Wnt-related genes was observed in both decidual and trophoblast cells using PCR array, with remarkably similar expression profiles. Co-culture induced altered expression of several Wnt-related proteins, with the Wnt inhibitors sFPR4 and DKK1 being among the most differentially expressed genes. Media concentrations of sFRP4 and DKK1 were increased with co-culture, coincident with a decrease in canonical Wnt signalling activity. Expression of PTGS1 mRNA and COX1 protein was also increased with co-culture as were media PGE2 concentrations; these changes were replicated by addition of exogenous DKK1 and sFRP4. Collectively, these data suggest that paracrine interactions between decidua and trophoblast stimulate Wnt antagonist secretion leading to increased placental prostaglandin production. This may be important for implantation and placental function.

Two competing theories address the influence of foetal testosterone on cerebral laterality: one proposing exposure to high foetal testosterone concentrations is related to atypical lateralisation (Geschwind–Galaburda hypothesis), the other that high foetal testosterone concentrations exaggerate typical lateralisation (callosal hypothesis). The current study examined the relationship between cord testosterone concentrations and cerebral laterality for language and spatial memory in adulthood. Male participants with high (>0.15 nmol) and low (<0.10 nmol) cord testosterone levels were invited to take part in the study (n = 18 in each group). Cerebral laterality was measured using functional Transcranial Doppler ultrasonography, while participants completed word generation and visual short-term memory tasks. Typical left lateralisation of language was more common in the high-testosterone group than in the low-testosterone group, χ2 = 4.50, df = 1, p = 034. Spatial memory laterality was unrelated to cord testosterone level. Our findings indicate that foetal testosterone exposure is related to language laterality in a direction that supports the callosal hypothesis.

Accurately measuring hormone exposure during prenatal life presents a methodological challenge and there is currently no “gold standard” approach. Ideally, circulating fetal hormone levels would be measured at repeated time points during pregnancy. However, it is not currently possible to obtain fetal blood samples without significant risk to the fetus, and therefore surrogate markers of fetal hormone levels must be utilized. Umbilical cord blood can be readily obtained at birth and largely reflects fetal circulation in late gestation.This review examines the accuracy and biological interpretation of the measurement of androgens and estrogens in cord blood. The use of cord blood hormones to understand and investigate human development is then discussed.

Human choriocarcinoma-derived BeWo cells express high levels of breast cancer resistance protein (BCRP/ABCG2) with no functional P-glycoprotein (P-gp) (ABCB1) activity, making them a potential model to study bidirectional ABCG2-mediated drug transport. However, the original BeWo clone (B24) available to researchers does not form confluent monolayers with tight junctions required by the model. Our aim was to adapt culture conditions to attempt to generate confluent BeWo monolayers for drug transport studies using the standard B24 clone. BeWo cells (B24; American Type Culture collection [ATCC]) were cultured in six-well plates or polycarbonate millicell inserts in a number of media formulations, growth supplements, and basement membrane substitutes. Cells were examined for confluence by microscopy, and transepithelial electrical resistance (TEER) was measured daily; monolayer permeability was assessed when TEER had stabilized. Optimal growth rates were achieved in culture conditions consisting of Medium 199 (M199) supplemented with epidermal growth factor (EGF; 20 ng/mL), vitamin supplements, and 10% fetal calf serum (FCS) with collagen coating. A TEER of 170 Ω in 0.6 cm2 inserts was achieved 2 weeks after seeding under optimal conditions. The cell-impermeable diffusion marker 5(6) carboxy-2,7dichlorodihydrofluorescein (C-DCDHF) had a permeability coefficient of 3.5 x 10-6 cm/s, indicative of minimal paracellular permeability. ABCG2 expression, as determined by immunoblotting, remained unaffected by confluency. In conclusion, we describe culture conditions for the B24 BeWo clone that facilitate the formation of monolayers with tighter junctions and reduced paracellular transport compared to previously published models. These growth conditions provide a good model of ABCG2-mediated drug transport in a human placental cell line.

Sphingosine and sphingosine-1-phosphate (S1P) are involved in regulating cell differentiation. This study postulated that changes in sphingolipid biosynthesis and metabolism are important in trophoblast syncytialization and therefore examined the production, metabolism and actions of sphingosine and S1P during spontaneous trophoblast differentiation and fusion in vitro. Significantdeclines in intracellular sphingosine concentration (P 0.05) and sphingosine kinase 1 (SPHK1) expression (P 0.01) were observed during trophoblast syncytialization. Secreted S1P concentrations dropped steeply after 72 h, before rising to basal concentrations with syncytialization. Intracellular S1P concentrations were undetectable throughout. Treating cells with exogenous sphingosine (P 0.01), S1P (P 0.001) or a specific SPHK1 inhibitor (P 0.05) for up to 72 h in culture significantly inhibited trophoblast differentiation (measured as reduced human chorionic gonadotrophin production); effects on other biochemical and morphological markers of differentiation were absent or inconsistent. Phosphorylation of Akt, an established down-stream target of S1P that spontaneously declines with trophoblast differentiation, was markedly reduced by S1P (P 0.05). In conclusion, changes in the sphingosine–S1P pathway are involved in the regulation of trophoblast differentiation in term human placenta. Dysregulation of sphingolipid homeostasis could, therefore, disrupt placental formation and function with deleterious consequences for pregnancyoutcome.

Sphingolipid mediators such as ceramide are pleiotropic regulators of cellular growth, differentiation and apoptosis. We investigated the role of ceramide biosynthesis, metabolism and actions in term human cytotrophoblasts syncytialized over 7 days in culture. Intracellular C16 ceramide levels increased modestly after 3 days in culture, then declined. Ceramidase was present at particularly high levels in syncytialized trophoblasts; inhibition of ceramidase reduced the degree of cell fusion. Exposure to short chain C8 ceramide or aSMase enhanced secretion of the differentiation marker hCG without affecting fusion or cell viability. In contrast, pharmacological inhibition of ceramidase reduced the extent of fusion. Inhibition of the ceramide-responsive JNK and PP2A pathways did not abolish the effects of ceramide, and JNK phosphorylation was unresponsive to ceramide; however, ceramide significantly inhibited phosphorylation of Akt. This study suggests that changes in ceramide biosynthesis and metabolism play a differential role in the biochemical and morphological features of trophoblast differentiation.

Endocannabinoids have been implicated in the mechanisms of implantation, maintenance of pregnancy, and parturition in women. Intrauterine prostaglandin production and actions are also critical in each of these mechanisms. Hence, we have evaluated the effects of cannabinoids on prostaglandin biosynthesis by human gestational membranes. Explants of term amnion and choriodecidua were established and treated with the endogenous endocannabinoids 2-arachidonoyl glycerol and anandamide, as well as the synthetic cannabinoid CP55,940, to determine their ability to modulate PGE(2) production. The explants were also treated with CP55,940 in the presence of either SR141716A (a potent and selective antagonist of the cannabinoid receptor CB1) or NS398 [a cyclooxygenase (COX)-2 inhibitor] to determine whether any observed stimulation of PGE2 production was mediated through the CB1-receptor and/or COX-2 activity. All three cannabinoids caused a significant increase in PGE2 production in the amnion but not in the choriodecidua. However, separated fetal ( chorion) explants responded to cannabinoid treatment in a similar manner to amnion, whereas maternal ( decidual) explants did not. The enhanced PGE2 production caused by CP55,940 was abrogated by cotreatment with either SR141716A or NS398, illustrating that the cannabinoid action on prostaglandin production in fetal membranes is mediated by CB1 agonism and COX-2. Data from Western blotting show that cannabinoid treatment results in the upregulation of COX-2 expression. This study demonstrates a potential role for endocannabinoids in the modulation of prostaglandin production in late human pregnancy, with potentially important implications for the timing and progression of term and preterm labor and membrane rupture.

Free to read at publisher's site. Preeclampsia is a serious and life-threatening pregnancy complication. Reduced uteroplacental perfusion and oxygen tension, impaired trophoblast differentiation and invasion, and altered placental production of immunomodulators and growth factors are all considered to be important aspects in the aetiology of the condition. The placenta expresses a variety of pro and anti-inflammatory cytokines, adipokines and cytokine-like angiogenic growth factors, production of which is altered in preeclampsia, driven ( at least in part) by hypoxia. Altered levels of cytokines have been measured in the circulation of women with preeclampsia, although for reasons that are not always apparent much of the data are disturbingly inconsistent. While the placenta undoubtedly makes an important contribution to plasma cytokine levels, production by maternal peripheral blood mononuclear cells ( PBMCs) and other tissues is also likely to be significant, although to what extent remains undetermined. Increased placental expression of soluble receptors occurs with preeclampsia, resulting in elevated circulating concentrations which confer impaired angiogenesis, deficient placental vascularisation, increased placental apoptosis and endothelial dysfunction. The extent to which these changes reflect a response to the disorder, as opposed to being a causative factor in the development of maternal disease, is a matter of some debate. Nevertheless, convincing evidence is now accruing that autocrine/paracrine interactions between placental cytokines/growth factors and the maternal endothelium play a central role in the pathogenesis of preeclampsia.

Free to read at publisher's site. Context: The importance of prostaglandin ( PG) signaling pathways to the maintenance of pregnancy and initiation of labor is well recognized. However, the complexity of these pathways and the mechanism(s) of their coordinated regulation in physiological and pathological conditions are only now being appreciated. Objectives: In this report we provide new evidence of a complete pathway for the biosynthesis and actions of PGD(2) and its metabolites within human gestational tissues. Materials and Methods: Using immunohistochemistry and Northern and Western blotting, we demonstrate the dynamic regulation of H-type PGD synthase (PGDS) in placenta during gestation; in contrast, L-type PGDS and its PG products were detected in amniotic fluid, with increased amounts associated with labor. Results: Placental tissues were shown to express both forms of the PGD(2) receptor identified to date, D prostanoid(1) (DP(1)) and DP(2)/chemotactic receptor on type 2 helper T cells, with a distribution consistent with the villous placenta being a major target, as well as source, of PGD(2). In vitro, placental PGD2 production was shown to be stimulated upon inflammatory activation, whereas PGD(2) and its J series metabolites exerted potent inhibitory effects on placental cytokine production. Conclusions: These findings suggest that PGDS-derived prostanoids play important physiological roles in the placenta, such as immunoregulation and feto-placental communication, while potentially having a regulatory role in the processes of parturition.

Free to read at publsiher's site. Decreased suppressors of cytokine signaling (SOCS) activity in human gestational tissues may play a part in the onset/progression of term labor. Since SOCS proteins negatively regulate cytokine-mediated inflammatory processes, we hypothesized that SOCS proteins are elevated in gestational tissues from spontaneous preterm deliveries with intrauterine infection. SOCS1, -2 and -3 mRNAs and proteins were detectable by RT-PCR and immunoblotting respectively, in preterm amnion, choriodecidua and placenta, irrespective of infection status. Immunoperoxidase staining localized SOCS1, -2 and -3 to all cell types of the gestational membranes, with infiltrating leukocytes reacting strongly in infected tissues. In villous placenta, SOCS was immunolocalized to the syncytiotrophoblast with marked staining of round mesenchymal cells, possibly Hofbauer cells. Nuclear SOCS staining was seen in amnion, chorion and placental syncytiotrophoblasts. SOCS proteins were, in general, significantly more abundant in placenta compared with amnion or choriodecidua. Placental SOCS1 and interleukin-1 beta concentrations were positively correlated (r(2)=0(.)47; P < 0(.)05). However, no changes in SOCS levels in any tissues were observed with intrauterine infection. The relatively large amounts of SOCS proteins in the placenta may reflect a placenta-specific immuno-protective response to minimize the elaboration and effects of cytokines with potential to harm the placenta and fetus. Lack of labor-associated changes in SOCS levels suggests that the regulation of SOCS expression in preterm gestational tissues differs from those at term, perhaps reflecting roles in regulating placental somatotropic responses.

15-Deoxy Delta(12,14)- prostaglandin J(2) (15d-PGJ(2)), an activator of peroxisome proliferator-activated receptor (PPAR)-gamma and -delta, is a prostanoid metabolite with anti-inflammatory actions. In intrauterine tissues, proinflammatory cytokines and prostaglandins have been identified as playing key roles in the maintenance of pregnancy and the onset of labor. We investigated and compared the early (<3 h) effects of 15d-PGJ(2) with rosiglitazone (PPAR-gamma ligand) and 2-methyl-4-((4-methyl-2-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl)- methylsulfanyl) phenoxy-acetic acid (GW501516) (PPAR-delta ligand) on interleukin (IL)-1 beta-induced prostaglandin and cytokine production by amnion-derived WISH cells. We show that 15d-PGJ(2) exerts differential effects depending on concentration. At low concentrations (<0.1 mu M), 15d-PGJ(2) inhibited IL-1 beta stimulated prostaglandin E-2 (PGE(2)) but not cytokine (IL-6/IL-8) production or cyclooxygenase-2 (COX-2) expression. This effect was attenuated by a PPAR-gamma inhibitor [2-chloro-5-nitro-N-phenylbenzamide (GW9662)], by transfection with a dominant-negative PPAR construct, and was reproduced by the PPAR-gamma ligand rosiglitazone. At higher concentrations (1 - 10 mu M), 15d-PGJ(2) inhibited IL-1 beta-stimulated PGE(2) and cytokine production and COX-2 expression, and this effect was not blocked by GW9662. Rosiglitazone at high concentrations ( 1 - 10 mu M) stimulated PGE(2) production in the absence or presence of the dominant-negative PPAR. The PPAR-delta ligand GW501516 also inhibited IL-1 beta-stimulated PGE(2) production but only at high concentrations (1 mu M). IL-1 beta-induced nuclear factor-kappa B (NF-kappa B) DNA binding activity was significantly inhibited by 15d-PGJ(2) ( 10 mu M) and GW501516 ( 1 mu M) but increased with 10 mu M rosiglitazone. We conclude that 1) at low concentrations, 15d-PGJ(2) acts through a PPAR-gamma signaling pathway; b) at higher concentrations, its actions are mediated most likely t