Alterations to Placental Glucocorticoid Receptor Expression with Alcohol Consumption.

Maternal alcohol consumption during pregnancy results in elevated vulnerability to intrauterine growth restriction, preterm birth, miscarriage, and stillbirth. Many of the detrimental effects of fetal alcohol exposure may be mediated through placental dysfunction; however, the exact mechanisms remain unknown. Here, we aimed to determine the effect of maternal alcohol exposure prior to and during early pregnancy on placental glucocorticoid receptor (GR) isoforms, associated GR regulated genes, and infant outcomes. Participants carrying singleton fetuses (n = 113) were recruited during early pregnancy. Amount and type of alcohol consumed over the last 12 months were obtained at 18 weeks of gestation. The level of drinking was separated into none (0 g/day), low (< 10 g/day), moderate (10-100 g/day), and heavy (> 100 g/day). At delivery, placental weight, infant sex, birthweight, and head circumference were recorded. Placental GR isoforms and genes involved in downstream signalling pathways were quantified. The majority of women (70.8%) consumed alcohol. Of these, most consumed low (48.8%) or moderate (37.5%) amounts. Placental weight was unaffected by alcohol consumption, but infants born to heavy drinkers tended to be lighter at birth. In female, but not male, placentae, maternal alcohol consumption resulted in increased GRαC and decreased GRαD1 cytoplasmic expression. In both female and male placentae, a dampened inflammatory response was evident with maternal alcohol consumption, involving downregulated IL6R and upregulated POU2F2 gene expression, respectively. Maternal alcohol consumption in the months prior to, and/or during early, pregnancy alters placental GR isoform and expression of some inflammatory genes in a sex-specific manner.

Pharmacogenomics of genetic polymorphism within the genes responsible for SARS-CoV-2 susceptibility and the drug-metabolising genes used in treatment.

The ongoing outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represents a significant challenge to international health. Pharmacogenomics aims to identify the different genetic variations that exist between individuals and populations in order to determine appropriate treatment protocols to enhance the efficacy of drugs and reduce their side-effects. This literature review provides an overview of recent studies of genetic polymorphisms in genes that mediate the SARS-CoV-2 infection mechanism (ACE1, ACE2, TMPRSS2 and CD26). In addition, genetic variations in the drug-metabolising enzyme genes of several selected drugs used in the treatment of COVID-19 are summarised. This may help construct an effective health protocol based on genetic biomarkers to optimise response to treatment. Potentially, pharmacogenomics could contribute to the development of effective high-throughput assays to improve patient evaluation, but their use will also create ethical, medical, regulatory, and legal issues, which should now be considered in the era of personalised medicine.

Review: Placental adaptations to the presence of maternal asthma during pregnancy.

Asthma is a highly prevalent chronic medical condition affecting an estimated 12% of pregnant, women each year, with prevalence of asthma greatest (up to 16%) among the socially disadvantaged. Maternal asthma is associated with significant perinatal morbidity and mortality including preterm births, neonatal hospitalisations and low birthweight outcomes each year. We have identified that the placenta adapts to the presence of chronic, maternal asthma during pregnancy in a sex specific manner that may confer sex differences in fetal outcome. The male fetus was at greater risk of a poor outcome than a female fetus in the presence of maternal asthma and an acute inflammatory event such as an asthma exacerbation. This review will examine the role of sex specific differences in placental function on fetal growth and survival.

Review: The role of multiple placental glucocorticoid receptor isoforms in adapting to the maternal environment and regulating fetal growth.

The physiological mechanisms that confer different outcomes in morbidity and mortality of the fetus exposed to stressful environments may be driven by significant differences in the expression and function of the placental glucocorticoid receptor (GR). The recent discovery that the placenta contains at least 8 different isoforms of the GR raises questions about the regulation and physiological relevance of the many GR variants expressed in the placenta. The current data also highlights that individual differences in glucocorticoid sensitivity, variations in the effect of different complications of pregnancy on birth outcomes and sex differences in the response to stress, may all be dependent on a specific GR isoform expression profile. This review will investigate the current state of knowledge of GR isoforms in the placenta and discuss the potential role of these multiple isoforms in regulating glucocorticoid sensitivity.

Expression of eight glucocorticoid receptor isoforms in the human preterm placenta vary with fetal sex and birthweight.

INTRODUCTION: Administration of betamethasone to women at risk of preterm delivery is known to be associated with reduced fetal growth via alterations in placental function and possibly direct effects on the fetus. The placental glucocorticoid receptor (GR) is central to this response and recent evidence suggests there are numerous isoforms for GR in term placentae. In this study we have questioned whether GR isoform expression varies in preterm placentae in relation to betamethasone exposure, fetal sex and birthweight. METHODS: Preterm (24-36 completed weeks of gestation, n = 55) and term placentae (>37 completed weeks of gestation, n = 56) were collected at delivery. Placental GR expression was examined using Western Blot and analysed in relation to gestational age at delivery, fetal sex, birthweight and betamethasone exposure. Data was analysed using non-parametric tests. RESULTS: Eight known isoforms of the GR were detected in the preterm placenta and include GRα (94 kDa), GRß (91 kDa), GRα C (81 kDa) GR P (74 kDa) GR A (65 kDa), GRα D1-3 (50-55 kDa). Expression varied between preterm and term placentae with a greater expression of GRα C in preterm placentae relative to term placentae. The only sex differences in preterm placentae was that GRα D2 expression was higher in males than females. There were no alterations in preterm placental GR expression in association with betamethasone exposure. DISCUSSION: GRα C is the isoform involved in glucocorticoid induced apoptosis and suggests that its predominance in preterm placentae may contribute to the pathophysiology of preterm birth.

Experimental and modeling study of the phase behavior of (methane + CO2 + water) mixtures.

In this work we report phase equilibrium measurements on the system (methane + carbon dioxide + water) carried out with a high-pressure quasi-static-analytical apparatus. The measurements have been made under conditions of two-phase vapor-liquid equilibrium, three-phase vapor-liquid-liquid equilibrium (VLLE), and four-phase vapor-liquid-liquid-hydrate equilibrium. The compositions of three coexisting fluid phases have been obtained along eight isotherms at temperatures from (285.15 to 303.5) K and at pressures up to either the upper critical end point (UCEP) or up to the hydrate formation locus. Compositions of coexisting vapor and liquid phases have been obtained along three isotherms at temperatures from (323.15 to 423.15) K and pressures up to 20 MPa. The quadruple curve, along which hydrates coexist with the three fluid phases, was also measured along its entire length. The VLLE data obtained for this mixture have been compared with the predictions of the statistical associating fluid theory for potentials of variable range (SAFT-VR), implemented with the square-well potential and using parameters fitted to pure-component and binary-mixture data. Specifically, we used the SAFT-VR parameters reported by Míguez and co-workers [Míguez, J. M.; dos Ramos, M. C.; Piñeiro, M. M.; Blas, F. J. J. Phys. Chem. B 2011, 115, 9604]. The pressure along the quadruple curve was compared with the predictions of two different thermodynamic models. Furthermore, a detailed study of the ternary mixtures was carried out based on comparison with available ternary data of the type (CO2 + n-alkane + water) and available data for the constituent binary subsystems. In this way, we analyzed the observed effects on the solubility when the n-alkane component was changed or a third component was added.

The human placenta expresses multiple glucocorticoid receptor isoforms that are altered by fetal sex, growth restriction and maternal asthma.

INTRODUCTION: We have previously identified sex-specific differences in the fetal-placental response to cortisol. Our recent studies suggest that this differential response to cortisol is driven by differences in glucocorticoid receptor (GR) protein function rather than through changes in gene transcription or protein expression. METHODS: This study was designed to define whether the human placenta expresses different isoforms of the GR and whether expression was altered by fetal sex and maternal asthma. Asthma and non-asthma pregnant women were prospectively recruited at their first antenatal visit and placentae collected at delivery. Placental GR expression was examined in relation to maternal asthma, fetal sex and birthweight. RESULTS: Twelve specific bands for the GR were identified at molecular weights of 94, 91, 81, 74, 69, 68, 65, 60, 55, 50, 48 and 38 kDa. The 12 isoforms were localised to the placental trophoblast and expression varied in relation to cellular location in either the cytoplasm or nucleus, fetal sex, fetal size and the presence and absence of maternal asthma. CONCLUSION: This is the first study to identify the presence of several protein isoforms of the GR in the human placenta. The data suggest glucocorticoid resistance observed in male placentae may be mediated through increased GRß, GR A and GR P localisation to the nucleus. While female placentae may be more sensitive to cortisol in the presence of maternal asthma through a decrease in GRß and an enhancement GRα activity via an interaction with GRα D3 and GRα C.