The Importance of Antioxidant Micronutrients in Pregnancy

Pregnancy places increased demands on the mother to provide adequate nutrition to the growing conceptus. A number of micronutrients function as essential cofactors for or themselves acting as antioxidants. Oxidative stress is generated during normal placental development; however, when supply of antioxidant micronutrients is limited, exaggerated oxidative stress within both the placenta and maternal circulation occurs, resulting in adverse pregnancy outcomes. The present paper summarises the current understanding of selected micronutrient antioxidants selenium, copper, zinc, manganese, and vitamins C and E in pregnancy. To summarise antioxidant activity of selenium is via its incorporation into the glutathione peroxidase enzymes, levels of which have been shown to be reduced in miscarriage and preeclampsia. Copper, zinc, and manganese are all essential cofactors for superoxide dismutases, which has reduced activity in pathological pregnancy. Larger intervention trials are required to reinforce or refute a beneficial role of micronutrient supplementation in disorders of pregnancies

Hepatic caveolin-1 is enhanced in Cyp27A1/ApoE double knockout mice

Sterol 27-hydroxylase (CYP27A1) is involved in bile acid synthesis and cholesterol homoeostasis. Cyp27a1(−/−)/Apolipoprotein E(−/−) double knockout mice (DKO) fed a western diet failed to develop atherosclerosis. Caveolin-1 (CAV-1), the main component of caveolae, is associated with lipid homoeostasis and has regulatory roles in vascular diseases. We hypothesized that liver CAV-1 would contribute to the athero-protective mechanism in DKO mice. Cyp27a1(+/+)/ApoE(−/−) (ApoE KO), Cyp27a1(+/−)/ApoE(−/−) (het), and DKO mice were fed a western diet for 2 months. Atherosclerotic plaque and CAV-1 protein were quantified in aortas. Hepatic Cav-1 mRNA was assessed using qPCR, CAV-1 protein by immunohistochemistry and western blotting. Total hepatic and plasma cholesterol was measured using chemiluminescence. Cholesterol efflux was performed in RAW264.7 cells, using mice plasma as acceptor. CAV-1 protein expression in aortas was increased in endothelial cells of DKO mice and negatively correlated with plaque surface (P < 0.05). In the liver, both CAV-1 protein and mRNA expression doubled in DKO, compared to ApoE KO and het mice (P < 0.001 for both) and was negatively correlated with total hepatic cholesterol (P < 0.05). Plasma from DKO, ApoE KO and het mice had the same efflux capacity. In the absence of CYP27A1, CAV-1 overexpression might have an additional athero-protective role by partly overcoming the defect in CYP27A1-mediated cholesterol efflux

Androgens Tend to Be Higher, but What about Altered Progesterone Metabolites in Boys and Girls with Autism?

BACKGROUND Evidence exists that steroid hormones are altered in individuals with autism, especially androgens. Despite lower prevalence in girls than boys, evidence of potential alterations in progesterone metabolites is sparse, so the aim of this study was to elucidate different progesterone metabolites in affected children with autism versus healthy controls. MATERIAL AND METHODS Circadian urine samples from 48 boys and 16 girls with autism spectrum disorders and a matched case-control group were analysed for progesterone metabolites by gas chromatography-mass spectrometry and normalised for creatinine excretion. RESULTS In boys with autism, the majority of progesterone metabolites were reduced, such as progesterone, 6a-OH-3a5b-TH-progesterone, or 20a-DH-progesterone (p &lt; 0.01 for all). In girls with autism, a similar pattern of reduction in progesterone metabolites was detected; however, potentially due to the relatively small sample, this pattern was only detectable on the level of a trend. DISCUSSION As stated, androgen levels are higher in boys and girls with autism, but evidence for progesterone metabolites is much sparser. The pattern of a decrease in progesterone metabolites suggests the existence of an altered routing of steroid metabolites, probably in combination with a dysregulation of the HPAG axis. As, recently, increased CYP17A1 activity has been suggested, the stronger routing towards androgens is further implied in line with our findings of lower progesterone concentrations in boys and girls with autism than healthy controls

Reduced selenium concentrations and glutathione peroxidase activity in preeclamptic pregnancies

Preeclampsia is a pregnancy-specific condition affecting 2-7% of women and a leading cause of perinatal and maternal morbidity and mortality. Preeclampsia may also predispose the fetus to increased risks of adult cardiovascular disease. Selenium, acting through the selenoprotein glutathione peroxidases, has critical roles in regulating antioxidant status. Recent reports implicate poor maternal selenium status as a nutritional factor predisposing the mother to preeclampsia but the fetus and placenta have not been studied in tandem. Measurement of selenium concentrations, expression and activity levels of glutathione peroxidase and markers of oxidative stress were performed on maternal and umbilical venous blood samples or the placenta from 27 normal pregnant, 25 preeclamptic and 22 healthy age-matched non-pregnant women. The results of this study revealed highly significant reductions in serum selenium concentrations and plasma glutathione peroxidase activity in pregnancy per se compared to non-pregnant controls. Moreover, these levels were further decreased in the preeclamptic mothers and babies compared to normal pregnancies. Umbilical venous selenium was particularly low (42.1±11.8 and 29.0 ± 9.9 mug/L; mean ±s.d.; P<0.05). Both mother and baby had significantly increased levels of markers for oxidative stress in the preeclamptic group. The placental glutathione peroxidase activity and immunohistochemical staining were also reduced in the preeclampsia placentae. Oxidative stress associated with preeclampsia may be a consequence of reduced antioxidant defence pathways specifically involving glutathione peroxidases, perhaps linked to reduced selenium availability. Reduced glutathione peroxidases could be associated with increased generation of toxic lipid peroxides contributing to the endothelial dysfunction and hypertension of preeclampsia

42 Negative correlation between PlGF and Endocan-1 in women with preeclampsia

Introduction: Endocan-1 is a soluble proteoglican specifically expressed in endothelial cells, a biomarker/predictor of vascular endothelial related pathologies, as pre-eclampsia (PE). PlGF is an angiogenic factor, and a marker of placental dysfunction, which is down regulated in women with PE. We hypothesized that Endocan-1 and PlGF levels would be negatively correlated in pregnant women with PE. Objectives: To analyse Endocan-1 and PlGF levels in maternal plasma in normotensive and women with PE and test the correlation between the findings in the third trimester of pregnancy. Methods: Endocan-1 and PlGF levels were measured in maternal plasma from normotensive (n= 67) and PE (n= 50) women using MagPlexTH-C microspheres system. Data was analysed by ANCOVA, adjusted for BMI, gestational age and maternal age. To estimate the difference between groups, mean ratio (MR) and confidence interval (CI) of 95% was calculated. Analysis between Endocan-1 levels and PlGF were made by Pearson correlation. The null hypothesis was rejected when p < 0.05. Results: Higher concentrations of Endocan-1 were found in maternal plasma in PE (MR = 1.49; 95% CI: 1.19–1.85,p= 0.001), with a moderate effect size (Cohen’s D = 0.84). When women with superimposed PE and HELLP syndrome were excluded, lower levels of PlGF were found in the PE group (MR = 0.38, 95% CI: 0.15–0.95 p = 0.041). A strong negative correlation between Endocan-1 e PlGF in the entire group (r=-0.605; p < 0.001); as well as in PE group (r=-0.545; p < 0.001) was observed. Conclusion: Endocan-1 levels are increased in patients with PE and are negatively correlated with PlGF levels. These data could be related to hypoxemia and fetal growth restriction (seen by lower PlGF levels), leading to a systemic response in order to find a volumetric compensation; leading to endothelial lesions (seen as the upregulation of Endocan-1). Thus, it is important to analyse angiogenic and proinflamatory molecules concomitantly in women with PE, in order to better understand the disease pathophysiology. In this case, both molecules are strong potentials as specific PE biomarkers

Human placental renin-angiotensin system in normotensive and pre-eclamptic pregnancies at high altitude and after acute hypoxia-reoxygenation insult.

A functioning placental renin-angiotensin system (RAS) appears necessary for uncomplicated pregnancy and is present during placentation, which occurs under low oxygen tensions. Placental RAS is increased in pre-eclampsia (PE), characterised by placental dysfunction and elevated oxidative stress. We investigated the effect of high altitude hypoxia on the RAS and hypoxia-inducible factors (HIFs) by measuring mRNA and protein expression in term placentae from normotensive (NT) and PE women who delivered at sea level or above 3100 m, using an explant model of hypoxia-reoxygenation to assess the impact of acute oxidative stress on the RAS and HIFs. Protein levels of prorenin (P = 0.049), prorenin receptor (PRR; P = 0.0004), and angiotensin type 1 receptor (AT1R, P = 0.006) and type 2 receptor (AT2R, P = 0.002) were all significantly higher in placentae from NT women at altitude, despite mRNA expression being unaffected. However, mRNA expression of all RAS components was significantly lower in PE at altitude than at sea level, yet PRR, angiotensinogen (AGT) and AT1R proteins were all increased. The increase in transcript and protein expression of all the HIFs and NADPH oxidase 4 seen in PE compared to NT at sea level was blunted at high altitude. Experimentally induced oxidative stress stimulated AGT mRNA (P = 0.04) and protein (P = 0.025). AT1R (r = 0.77, P < 0.001) and AT2R (r = 0.81, P < 0.001) mRNA both significantly correlated with HIF-1β, whilst AT2R also correlated with HIF-1α (r = 0.512, P < 0.013). Our observations suggest that the placental RAS is responsive to changes in tissue oxygenation: this could be important in the interplay between reactive oxygen species as cell-signalling molecules for angiogenesis and hence placental development and function.HDM is supported by an ERA-EDTA Fellowship (ERA LTF 137-2013).This is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1113/JP27104

Maternal, Fetal, and Placental Selectins in Women With Pre-eclampsia; Association With the Renin-Angiotensin-System.

Selectins [endothelial (E), platelet (P), and leucocytes (L)] are a class of cell adhesion molecules, stimulated in response to inflammation. Pre-eclampsia is characterized by inflammation, and angiotensin II is pro-inflammatory. We hypothesized that circulating maternal and fetal concentrations and placental expression of selectins would be increased in women with pre-eclampsia and would be associated with the angiotensin receptors (AT1R and AT2R). Maternal and fetal blood and placental tissue was collected at delivery from White European normotensive controls (n = 17) and women with pre-eclampsia (n = 17). Soluble (s) E-, P- and L-selectin protein concentrations were measured by ELISA and placental protein expression was examined by immunohistochemistry. Maternal sE-selectin concentrations were increased in pre-eclampsia (P < 0.001); conversely fetal sE- and sP-selectin levels were lower in pre-eclampsia (P < 0.05 for both). Staining was mainly localized to the syncytiotrophoblast for all selectins. E-selectin expression was increased, while P-selectin was decreased in placental from pre-eclampsia (P < 0.05 for both); no differences were observed for L-selectin expression. Both E- and L-selectin were positively correlated (P < 0.008; P < 0.02) with AT2R placental expression, whilst P-selectin was negatively associated with AT1R (P < 0.005), all only in the pre-eclampsia group. This novel study reports maternal, fetal and placental expression of selectins in pre-eclampsia. The increased E-selectins reflect the endothelial dysfunction, characteristic of pre-eclampsia. In contrast, the reduced P-selectins and the positive association of placental AT2Rs with both E-and L-selectin in pre-eclampsia could be a protective mechanism to limit the endothelial dysfunction

Expression of voltage-dependent potassium channels in first trimester human placentae

Potassium channel α-subunits encoded by KCNQ1-5 genes form voltage-dependent channels (Kv7), modulated by KCNE1-5 encoded accessory proteins. The aim was to determine KCNQ and KCNE mRNA expression and assess protein expression/localisation of the KCNQ3 and KCNE5 isoforms in first trimester placental tissue. Placentae were obtained from women undergoing elective surgical termination of pregnancy (TOP) at 10 weeks’ (mid TOP) gestations. KCNQ1-5 expression was unchanged during the first trimester. KCNE5 expression increased in mid TOP vs. early TOP samples (P=0.022). This novel study reports mRNA and protein expression of Kv7 channels in first trimester placentae

Is the atherosclerotic phenotype of pre-eclamptic placentas due to altered lipoprotein concentrations and placental lipoprotein receptors?: role of a small-for-gestational-age phenotype

Artherosis of spiral arteries in uteroplacental beds from pre-eclamptic women resemble those of atherosclerosis, characterised by increased plasma lipids and lipoproteins. We hypothesised 1) lipoproteins receptors/transporter in placenta would be up-regulated in pre-eclampsia, associated with increased maternal and fetal lipoprotein concentrations; 2) expression of these would be reduced in pre-eclamptic placentae from women delivering small-for-gestational-age (SGA) infants. Placental biopsies, maternal and umbilical serum samples were taken from 27 normotensive and 24 pre-eclamptic women. Maternal/umbilical cord serum LDL; HDL; total cholesterol and triglycerides were measured. Placental mRNA expression of lipoprotein receptors/transporters were quantified using qRT-PCR. Protein localisation/expression of LRP-1 in the pre-eclamptic with/without SGA was measured by immunohistochemistry. Placental mRNA expression of all genes except PON-1, MTTP and PDIA2 were observed. No differences for any lipoprotein receptors/transporters were found between groups; however, in the pre-eclamptic group placental LRP-1 expression was lower in SGA delivering mothers (n = 7; P=0.036). LRP-1 protein was localised around fetal vessels and Hofbauer cells. This is the first detailed study of maternal/fetal lipoprotein concentrations and placental lipoprotein receptor mRNA expression in normotensive and pre-eclamptic pregnancies. These findings do not support a role of altered lipid metabolism in pre-eclampsia, but may be involved in fetal growth

A pilot study of alterations in oxidized angiotensinogen and antioxidants in pre-eclamptic pregnancy

© 2020, The Author(s). The oxidation status of angiotensinogen (AGT) may have a critical role in pre-eclampsia. We used a validated, quantitative, mass spectrometry-based method to measure the oxidized and total AGT levels in plasma of pre-eclamptic women (n = 17), normotensive-matched controls (n = 17), and healthy non-pregnant women (n = 10). Measurements of plasma glutathione peroxidase (GPx) activity and serum selenium concentrations were performed as markers of circulating antioxidant capacity. Higher proportions of oxidized AGT in plasma from pre-eclamptic women compared to matched normotensive pregnant controls (P = 0.006), whilst maintaining a similar total plasma AGT concentration were found. In the pre-eclamptic group, blood pressure were correlated with the proportion of oxidized AGT; no such correlation was seen in the normotensive pregnant women. Plasma GPx was inversely correlated with oxidized AGT, and there was an inverse association between serum selenium concentration and the proportion of oxidized AGT. This is the first time that oxidized AGT in human plasma has been linked directly to antioxidant status, providing a mechanism for the enhanced oxidative stress in pre-eclampsia. We now provide pathophysiological evidence that the conversion of the reduced form of AGT to its more active oxidized form is associated with inadequate antioxidant status and could indeed contribute to the hypertension of pre-eclampsia