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Maternal stress is a key risk factor for neurodevelopmental disorders, including schizophrenia and autism, which often exhibit a sex bias in rates of presentation, age of onset, and symptom severity. The placenta is an endocrine tissue that functions as an important mediator in responding to perturbations in the intrauterine environment and is accessible for diagnostic purposes, potentially providing biomarkers predictive of disease. Therefore, we have used a genome-wide array approach to screen placental expression across pregnancy for gene candidates that are sex-biased and stress-responsive in mice and translate to human tissue. We identifed O-linked- N -acetylglucosamine (O-GlcNAc) transferase (OGT), an X-linked gene important in regulating proteins involved in chromatin remodeling, as fitting these criteria. Levels of both OGT and its biochemical mark, O - GlcNAcylation, were significantly lower in males and further reduced by prenatal stress. Examination of human placental tissue found similar patterns related to X chromosome dosage. As a demonstration of the importance of placental OGT in neurodevelopment, we found that hypothalamic gene expression and the broad epigenetic microRNA environment in the neonatal brain of placental-specific hemizygous OGT mice was substantially altered. These studies identified OGT as a promising placental biomarker of maternal stress exposure that may relate to sex-biased outcomes in neurodevelopment.

Τhe intrauterine environment has a strong connection with the growing fetus and possible effects that can continue up to adulthood. Currently, stress is conceptualized as a modern teratogen. The overwhelming majority of studies indicate that maternal stress during pregnancy may have effects on pregnancy outcomes and fetal development, with long-lasting consequences on child and adult vulnerability to disease. Glucocorticoids are essential for regulating fetal development, growth, and metabolism. The two isoforms of 11beta-hydroxysteroid dehydrogenase enzyme (11β-HSD) mediate and regulate glucocorticoid actions and biological activity. It has not yet been fully elucidated whether maternal stress during pregnancy affects 11β-HSD isoenzyme activity and expression and results in possible adverse effects on fetal development, metabolism, and pregnancy outcomes. This review examines a possible pathophysiological mechanism by which maternal stress during pregnancy affects placental 11β-HSD isoenzyme activity, thereby causing adverse effects on the physiological status of pregnancy, fetal development, and metabolism. Furthermore, the main outcome of the review is the following: chronic and acute maternal stress during pregnancy affects the activity and the expression of placental 11β-HSD isoenzymes and has possible subsequent unfavorable results on preeclampsia, preterm birth, and fetuses with intrauterine growth restriction (IUGR) or small for gestational age (SGA) fetuses.

The liver of pregnant women undergoes physiological and pathological changes and the changes in liver enzyme activity and release reflect changes in serum enzymatic activity. We aimed to assess the activity of alcohol dehydrogenase (ADH) isoenzymes, and aldehyde dehydrogenase (ALDH) in the sera of women with intrahepatic cholestasis of pregnancy (ICP), the most common pregnancy-related liver disease. Serum samples were taken from 40 women with ICP in the second or third trimester of pregnancy. Serum samples were also obtained from 40 healthy pregnant women at the same time of pregnancy and 40 healthy non-pregnant women. Class I and II of ADH and ALDH activity was measured by a spectrofluorometric method. Class III, IV ADH and total ADH activity was measured by photometric methods. The total ADH activity was significantly higher in women with ICP than in healthy pregnant and non-pregnant women (about 42%). The median total activity of ADH was 1067 mU/l in women with ICP, 628 mU/l in healthy pregnant and 605 mU/l in non-pregnant women. A statistically significant increase in class I ADH isoenzymes was found in the sera of pregnant women with ICP. The median activity of this class in the ICP group increased about 62% and 80% in comparison to the healthy pregnant women and non-pregnant women, respectively. The activity of class I ADH isoenzymes in the sera of women with ICP is statistically significantly increased and may have a diagnostic significance.

Multiple pregnancies are prone to gestational diabetes mellitus (GDM). This study investigated the association between pregravid liver enzyme levels and the development of GDM in a twin pregnancy. Women who had the National Health Screening Examination and delivered their twin babies within one year were enrolled. Pregravid liver enzyme levels were divided into high and low level. Risks for developing GDM by high levels of liver enzymes were analyzed, in subgroups by pregravid obesity or metabolic syndrome. Among the 4348 twin pregnancies, 369 women (8.5%) developed GDM not requiring insulin treatment (GDM − IT), and 119 women (2.7%) developed GDM requiring insulin treatment(GDM + IT). High levels of pregravid GGT and ALT were related to risks of GDM + IT not only in women with obesity or metabolic syndrome (odds ratio[OR] 6.348, 95% confidence interval [CI] 2.579–15.624 and OR 6.879, 95% CI 2.232–21.204, respectively), but also in women without obesity (OR 3.05, 95% CI 1.565–5.946) or without metabolic syndrome (OR 3.338, 95% CI 1.86–5.992), compared to in women with low levels of those. However, there were no significant associations in the pregravid ALT and GGT levels and risks for development of GDM − IT, unrelated to pregravid obesity or metabolic syndrome. Therefore, this study suggests that women with high levels of pregravid GGT and ALT need to recognize their increased risk of GDM + IT, regardless of pregravid obesity or MetS, when they get pregnant twin.

Purpose: Fetal folate deficiency may increase the risk of subsequent childhood acute leukemia (AL), since folates are required for DNA methylation, synthesis, and repair, but the literature remains scarce. This study tested the hypothesis that maternal folic acid supplementation before or during pregnancy reduces AL risk, accounting for the SNPs rs1801133 (C677T) and rs1801131 (A1298C) in MTHFR and rs1801394 (A66G) and rs1532268 (C524T) in MTRR, assumed to modify folate metabolism. Methods: The nationwide registry-based case-control study, ESCALE, carried out in 2003-2004, included 764 AL cases and 1,681 controls frequency matched with the cases on age and gender. Information on folic acid supplementation was obtained by standardized telephone interview. The genotypes were obtained using high-throughput platforms and imputation for untyped polymorphisms. Odds ratios (OR) were estimated using unconditional regression models adjusted for potential confounders. Results: AL was significantly inversely associated with maternal folic acid supplementation before and during pregnancy (OR = 0.4; 95 % confidence interval: [0.3-0.6]). MTHFR and MTRR genetic polymorphisms were not associated with AL. However, AL was positively associated with homozygosity for any of the MTHFR polymorphisms and carriership of both MTRR variant alleles (OR = 1.6 [0.9-3.1]). No interaction was observed between MTHFR, MTRR, and maternal folate supplementation. Conclusion: The study findings support the hypothesis that maternal folic acid supplementation may reduce the risk of childhood AL. The findings also suggest that the genotype homozygous for any of the MTHFR variants and carrying both MTRR variants could be a risk factor for AL.

Synchronized preimplantation embryo development and passage through the oviduct into the uterus are prerequisites for implantation, dysregulation of which often leads to pregnancy failure in women. Cannabinoid/endocannabinoid signaling via cannabinoid receptor CB1 is known to influence early pregnancy. Here we provide evidence that a critical balance between anandamide synthesis by N-acylphosphatidylethanolamine-selective phospholipase D (NAPE-PLD) and its degradation by fatty acid amide hydrolase (FAAH) in mouse embryos and oviducts creates locally an appropriate \"anandamide tone\" for normal development of embryos and their oviductal transport. FAAH inactivation yielding higher anandamide or experimentally induced higher cannabinoid [(-)-Delta9-tetrahydrocannabinol] levels constrain preimplantation embryo development with aberrant expression of Cdx2, Nanog, and Oct3/4, genes known to direct lineage specification. Defective oviductal embryo transport arising from aberrant endocannabinoid signaling also led to deferred on-time implantation and poor pregnancy outcome. Intercrossing between wild-type and Faah-/- mice rescued developmental defects, not oviductal transport, implying that embryonic and maternal FAAH plays differential roles in these processes. The results suggest that FAAH is a key metabolic gatekeeper, regulating on-site anandamide tone to direct preimplantation events that determine the fate of pregnancy. This study uncovers what we believe to be a novel regulation of preimplantation processes, which could be clinically relevant for fertility regulation in women.

Iodine is an essential element trace for the synthesis of maternal thyroid hormones needed to support normal fetal development; it also acts as an antioxidant directly or induce antioxidant enzymes indirectly. Iodine deficiency and oxidative stress are associated with pregnancy complications. This study aimed to assess the urinary iodine concentration and its relationship with the antioxidant and oxidative stress status during gestation. Pregnant women were consecutively recruited from an obstetric clinic during all gestation trimesters, and urinary iodine concentration, antioxidant, and oxidative stress were determined. Results showed that 70 % of pregnant women have optimal iodine levels (150–200 μg/L), while approximately 30 % showed mild iodine deficiency (50–99 μg/L). Oxidative stress was significantly higher, and the antioxidant status was also compromised as evidenced by decreased total antioxidant status and superoxide dismutase (SOD) activity in pregnant women with mild iodine deficiency than pregnant women with optimal iodine levels. Significant positive correlations were noted between optimal iodine levels and total antioxidant status. Oxidative stress was significantly correlated with mild iodine deficiency. However, no significant correlation was found between iodine levels and SOD and catalase activities. In conclusion, for the first time, these data suggest a correlation between iodine levels and the antioxidant status during pregnancy.

MT1-MMP Expression in First-Trimester Placental Tissue Is Upregulated in Type 1 Diabetes as a Result of Elevated Insulin and Tumor Necrosis Factor-α Levels Ursula Hiden 1 , Elisabeth Glitzner 1 , Marina Ivanisevic 2 , Josip Djelmis 2 , Christian Wadsack 1 , Uwe Lang 1 and Gernot Desoye 1 1 Department of Obstetrics and Gynecology, Medical University of Graz, Austria 2 Department of Obstetrics and Gynecology, University Hospital, Petrova, Zagreb, Croatia Address correspondence and reprint requests to Ursula Hiden, MSc, PhD, Department of Obstetrics and Gynecology, Medical University of Graz, Auenbruggerplatz 14, 8036 Graz, Austria. E-mail: ursula.hiden{at}klinikum-graz.at Abstract OBJECTIVE —In pregestational diabetes, the placenta at term of gestation is characterized by various structural and functional changes. Whether similar alterations occur in the first trimester has remained elusive. Placental development requires proper trophoblast invasion and tissue remodeling, processes involving matrix metalloproteinases (MMPs) of which the membrane-anchored members (MT-MMPs) such as MT1-MMPs are key players. Here, we hypothesize a dysregulation of placental MT1-MMP in the first trimester of type 1 diabetic pregnancies induced by the diabetic environment. RESEARCH DESIGN AND METHODS —MT1-MMP protein was measured in first-trimester placentas of healthy ( n = 13) and type 1 diabetic ( n = 13) women. To identify potential regulators, first-trimester trophoblasts were cultured under hyperglycemia and various insulin, IGF-I, IGF-II, and tumor necrosis factor-α (TNF-α) concentrations in presence or absence of signaling pathway inhibitors. RESULTS —MT1-MMP was strongly expressed in first-trimester trophoblasts. In type 1 diabetes, placental pro–MT1-MMP was upregulated, whereas active MT1-MMP expression was only increased in late first trimester. In isolated primary trophoblasts, insulin, IGF-I, IGF-II, and TNF-α upregulated MT1-MMP expression, whereas glucose had no effect. The insulin effect was dependent on phosphatidylinositol 3-kinase, the IGF-I effect on mitogen-activated protein kinase, and the IGF-II effect on both. CONCLUSIONS —This is the first study reporting alterations in the first-trimester placenta in type 1 diabetes. The upregulated MT1-MMP expression in type 1 diabetes may be the result of higher maternal insulin and TNF-α levels. We speculate that the elevated MT1-MMP will affect placental development and may thus contribute to long-term structural alterations in the placenta in pregestational diabetes. DMEM, Dulbecco's modified Eagle's medium ECM, extracellular matrix ERK, extracellular signal–related kinase GRO, growth-regulated protein hCG, human chorionic gonadotropin HIF-1, hypoxia-inducible factor 1 IL, interleukin MAPK, mitogen-activated protein kinase MEK1, MAPK/ERK kinase 1 MMP, matrix metalloproteinase PI 3-kinase, phosphatidylinositol 3-kinase RPL30, ribosomal protein L30 TNF-α, tumor necrosis factor-α Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 17 October 2007. DOI: 10.2337/db07-0903. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted October 3, 2007. Received July 4, 2007. DIABETES

Tubal factor infertility (TFI) represents 36% of female infertility and genital infection by Chlamydia trachomatis (C. trachomatis) is a major cause. Although TFI is associated with host inflammatory responses to bacterial components, the molecular pathogenesis of Chlamydia-induced infertility remains poorly understood. We investigated the hypothesis that activation of specific cysteine proteases, the caspases, during C. trachomatis genital infection causes the disruption of key fertility-promoting molecules required for embryo development and implantation. We analyzed the effect of caspase inhibition on infertility and the integrity of Dicer, a caspase-sensitive, fertility-promoting ribonuclease III enzyme, and key micro-RNAs in the reproductive system. Genital infection with the inflammation- and caspase-inducing, wild-type C. trachomatis serovar L2 led to infertility, but the noninflammation-inducing, plasmid-free strain did not. We confirmed that caspase-mediated apoptotic tissue destruction may contribute to chlamydial pathogenesis. Caspase-1 or -3 deficiency, or local administration of the pan caspase inhibitor, Z-VAD-FMK into normal mice protected against Chlamydia-induced infertility. Finally, the oviducts of infected infertile mice showed evidence of caspase-mediated cleavage inactivation of Dicer and alteration in critical miRNAs that regulate growth, differentiation, and development, including mir-21. These results provide new insight into the molecular pathogenesis of TFI with significant implications for new strategies for treatment and prevention of chlamydial complications.

Background. It has been reported that pregnant women receiving protease inhibitor (PI)–based combination antiretroviral therapy (cART) have lower levels of progesterone, which put them at risk of adverse birth outcomes, such as low birth weight. We sought to understand the mechanisms involved in this decline in progesterone level. Methods. We assessed plasma levels of progesterone, prolactin, and lipids and placental expression of genes involved in progesterone metabolism in 42 human immunodeficiency virus (HIV)–infected and 31 HIV-uninfected pregnant women. In vitro studies and a mouse pregnancy model were used to delineate the effect of HIV from that of PI-based cART on progesterone metabolism. Results. HIV-infected pregnant women receiving PI-based cART showed a reduction in plasma progesterone levels (P= .026) and an elevation in placental expression of the progesterone inactivating enzyme 20-α-hydroxysteroid dehydrogenase (20αHSD; median, 2.5 artibrary units [AU]; interquartile range [IQR], 1.00–4.10 AU), compared with controls (median, 0.89 AU; IQR, 0.66–1.26 AU; P = .002). Prolactin, a key regulator of 20α-HSD, was lower (P = .012) in HIV-infected pregnant women. We observed similar data in pregnant mice exposed to PI-based cART. In vitro inhibition of 20α-HSD activity in trophoblast cells reversed PI-based cART–induced decreases in progesterone levels. Conclusions. Our data suggest that the decrease in progesterone levels observed in HIV-infected pregnant women exposed to PI-based cART is caused, at least in part, by an increase in placental expression of 20α-HSD, which may be due to lower prolactin levels observed in these women.