Maternal Diet High in Linoleic Acid Alters Renal Branching Morphogenesis and mTOR/AKT Signalling Genes in Rat Fetal Kidneys.

Linoleic acid (LA), an n-6 polyunsaturated fatty acid (PUFA), is obtained from the maternal diet during pregnancy, and is essential for normal fetal growth and development. A maternal high-LA (HLA) diet alters maternal and offspring fatty acids, maternal leptin and male/female ratio at embryonic (E) day 20 (E20). We investigated the effects of an HLA diet on embryonic offspring renal branching morphogenesis, leptin signalling, megalin signalling and angiogenesis gene expression. Female Wistar Kyoto rats were fed low-LA (LLA; 1.44% energy from LA) or high-LA (HLA; 6.21% energy from LA) diets during pregnancy and gestation/lactation. Offspring were sacrificed and mRNA from kidneys was analysed by real-time PCR. Maternal HLA decreased the targets involved in branching morphogenesis Ret and Gdnf in offspring, independent of sex. Furthermore, downstream targets of megalin, namely mTOR, Akt3 and Prkab2, were reduced in offspring from mothers consuming an HLA diet, independent of sex. There was a trend of an increase in the branching morphogenesis target Gfra1 in females (p = 0.0517). These findings suggest that an HLA diet during pregnancy may lead to altered renal function in offspring. Future research should investigate the effects an HLA diet has on offspring kidney function in adolescence and adulthood.

Maternal Diet High in Linoleic Acid Alters Offspring Lipids and Hepatic Regulators of Lipid Metabolism in an Adolescent Rat Model.

Linoleic acid (LA), an n-6 polyunsaturated fatty acid (PUFA), is essential for fetal growth and development. A maternal high LA (HLA) diet alters cardiovascular development in adolescent rats and hepatic function in adult rats in a sex-specific manner. We investigated the effects of an HLA diet on adolescent offspring hepatic lipids and hepatic lipid metabolism gene expression, and the ability of the postnatal diet to alter these effects. Female Wistar Kyoto rats were fed low LA (LLA; 1.44% energy from LA) or high LA (HLA; 6.21% energy from LA) diets during pregnancy and gestation/lactation. Offspring, weaned at postnatal day (PN) 25, were fed LLA or HLA and euthanised at PN40 (n = 6-8). Maternal HLA increased circulating uric acid, decreased hepatic cholesterol and increased hepatic Pparg in males, whereas only hepatic Srebf1 and Hmgcr increased in females. Postnatal (post-weaning) HLA decreased liver weight (% body weight) and increased hepatic Hmgcr in males, and decreased hepatic triglycerides in females. Maternal and postnatal HLA had an interaction effect on Lpl, Cpt1a and Pparg in females. These findings suggest that an HLA diet both during and after pregnancy should be avoided to improve offspring disease risk.

Dietary supplements, guideline alignment and biochemical nutrient status in pregnancy: Findings from the Queensland Family Cohort pilot study.

In high-income nations, multiple micronutrient (MMN) supplementation during pregnancy is a common practice. We aimed to describe maternal characteristics associated with supplement use and daily dose of supplemental nutrients consumed in pregnancy, and whether guideline alignment and nutrient status are related to supplement use. The Queensland Family Cohort is a prospective, Australian observational longitudinal study. Maternal characteristics, nutrient intake from food and supplements, and biochemical nutrient status were assessed in the second trimester (n = 127). Supplement use was reported by 89% of participants, of whom 91% reported taking an MMN supplement. Participants who received private obstetric care, had private health insurance and had greater alignment to meat/vegetarian alternatives recommendations were more likely to report MMN supplement use. Private obstetric care and general practitioner shared care were associated with higher daily dose of supplemental nutrients consumed compared with midwifery group practice. There was high reliance on supplements to meet nutrient reference values for folate, iodine and iron, but only plasma folate concentrations were higher in MMN supplement versus nonsupplement users. Exceeding the upper level of intake for folic acid and iron was more likely among combined MMN and individual supplement/s users, and associated with higher plasma concentrations of the respective nutrients. Given the low alignment with food group recommendations and potential risks associated with high MMN supplement use, whole food diets should be emphasized. This study confirms the need to define effective strategies for optimizing nutrient intake in pregnancy, especially among those most vulnerable where MMN supplement use may be appropriate.

A gut microbiome metabolite paradoxically depresses contractile function while activating mitochondrial respiration.

Trimethylamine-N-oxide (TMAO) is an end-product of gut microbiome metabolism linked to cardiovascular disease (CVD). However, precise cardiovascular influences of the TMAO concentrations reported in early or severe disease remain to be detailed. We investigated acute effects of TMAO on cardiac contractile, coronary and mitochondrial function. Male C57Bl/6 mouse hearts were Langendorff perfused to assess concentration-dependent effects of TMAO (1-300 µM) on left ventricular (LV) function, coronary flow and select protein expression. Effects of 10 µM and 100 µM TMAO on LV mitochondrial function were examined via respirometry. TMAO at 10-300 µM concentration-dependently depressed LV contractile function, with coronary flow paralleling changes in isovolumic pressure development. Direct coronary effects were evident at >30 µM TMAO in hearts performing minimal isovolumic work, although this response was reduced by >65%. In contrast, exposure to 10 µM or 100 µM TMAO increased mitochondrial complex I, II and maximal respiratory fluxes while appearing to reduce outer membrane integrity. Expression of phosphorylated AMPKα and total GSK-3ß declined. Thus, acute exposure of mouse hearts to TMAO levels reported in advanced CVD significantly inhibits cardiac contractility and induces modest coronary constriction while paradoxically overactivating mitochondrial respiration.

Potential biomarkers for late-onset and term preeclampsia: A scoping review.

Preeclampsia is a progressive, multisystem pregnancy disorder. According to the time of onset or delivery, preeclampsia has been subclassified into early-onset (<34 weeks) and late-onset (≥34 weeks), or preterm (<37 weeks) and term (≥37 weeks). Preterm preeclampsia can be effectively predicted at 11-13 weeks well before onset, and its incidence can be reduced by preventively using low-dose aspirin. However, late-onset and term preeclampsia are more prevalent than early forms and still lack effective predictive and preventive measures. This scoping review aims to systematically identify the evidence of predictive biomarkers reported in late-onset and term preeclampsia. This study was conducted based on the guidance of the Joanna Briggs Institute (JBI) methodology for scoping reviews. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension for scoping reviews (PRISMA-ScR) was used to guide the study. The following databases were searched for related studies: PubMed, Web of Science, Scopus, and ProQuest. Search terms contain "preeclampsia," "late-onset," "term," "biomarker," or "marker," and other synonyms combined as appropriate using the Boolean operators "AND" and "OR." The search was restricted to articles published in English from 2012 to August 2022. Publications were selected if study participants were pregnant women and biomarkers were detected in maternal blood or urine samples before late-onset or term preeclampsia diagnosis. The search retrieved 4,257 records, of which 125 studies were included in the final assessment. The results demonstrate that no single molecular biomarker presents sufficient clinical sensitivity and specificity for screening late-onset and term preeclampsia. Multivariable models combining maternal risk factors with biochemical and/or biophysical markers generate higher detection rates, but they need more effective biomarkers and validation data for clinical utility. This review proposes that further research into novel biomarkers for late-onset and term preeclampsia is warranted and important to find strategies to predict this complication. Other critical factors to help identify candidate markers should be considered, such as a consensus on defining preeclampsia subtypes, optimal testing time, and sample types.

Selenium Status: Its Interactions with Dietary Mercury Exposure and Implications in Human Health.

Selenium is an essential trace element in humans and animals and its role in selenoprotein and enzyme antioxidant activity is well documented. Food is the principal source of selenium, and it is important that selenium status in the body is adequately maintained for physiological functions. There has been increasing attention on the role of selenium in mitigating the toxic effects of mercury exposure from dietary intake in humans. In contrast, mercury is a neurotoxin, and its continuous exposure can cause adverse health effects in humans. The interactions of selenium and mercury are multi-factorial and involve complex binding mechanisms between these elements at a molecular level. Further insights and understanding in this area may help to evaluate the health implications of dietary mercury exposure and selenium status. This review aims to summarise current information on the interplay of the interactions between selenium and mercury in the body and the protective effect of selenium on at-risk groups in a population who may experience long-term mercury exposure.

Selenium Prevents Inflammation in Human Placenta and Adipose Tissue In Vitro: Implications for Metabolic Diseases of Pregnancy Associated with Inflammation.

Gestational diabetes mellitus (GDM) and maternal obesity are significant metabolic complications increasingly prevalent in pregnancy. Of major concern, both GDM and maternal obesity can have long-term detrimental impacts on the health of both mother and offspring. Recent research has shown that increased inflammation and oxidative stress are two features central to the pathophysiology of these metabolic conditions. Evidence suggests selenium supplementation may be linked to disease prevention in pregnancy; however, the specific effects of selenium on inflammation and oxidative stress associated with GDM and maternal obesity are unknown. Therefore, this study aimed to investigate the effect of selenium supplementation on an in vitro model of GDM and maternal obesity. Human placental tissue, visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were stimulated with either the bacterial product lipopolysaccharide (LPS) or the pro-inflammatory cytokine TNF-α. Selenium pre-treatment blocked LPS and TNF-α induced mRNA expression and secretion of pro-inflammatory cytokines and chemokines, while increasing anti-inflammatory cytokine and antioxidant mRNA expression in placenta, VAT and SAT. Selenium pre-treatment was also found to inhibit LPS- and TNF-α induced phosphorylation of ERK in placenta, VAT and SAT. These findings indicate that selenium may be able to prevent inflammation and oxidative stress associated with GDM and maternal obesity. Additional in vivo studies are required to identify the efficacy of selenium supplementation in preventing inflammatory pathways activated by GDM and maternal obesity and to elucidate the mechanism involved.

Transcriptional profiles of genes related to mitochondrial aging in placental pathologies.

As the placenta develops across gestation, the mitochondria and other organelles like the endoplasmic reticulum (ER) must continue to adapt to stressors such as oxidative stress. As pregnancy approaches term, these stressors may contribute to placental aging, including mitochondrial changes leading to cellular senescence. When these processes are exacerbated, pregnancy pathologies arise. This study aimed to identify correlations between genes related to mitochondria, ER and cellular senescence in placentae complicated by pregnancy complications. Placental samples from pregnancies classified as preterm, term, post-term, preterm with foetal growth restriction (FGR), preterm with preeclampsia (PE) and preterm with PE and FGR were used to measure gene expression of TOMM20, MFN1, TFAM, MFN2, PARK2, PINK1, EIF2AK3, TP53 and ERN1. MetaboAnalyst 5.0 was used to generate heatmaps, principal component analysis plots, correlation graphs and receiver operating characteristic analysis. This study found that genes-related mitochondrial dynamics and aging undergo changes in placentae affected by pregnancy pathologies. The TOMM20/PARK2 ratio may be a promising marker to discriminate between healthy and unhealthy placental tissue. Future studies should explore circulating biomarkers of mitochondrial aging and dysfunction as indicators of placental health.

Blood oxidative stress biomarkers in women: influence of oral contraception, exercise, and N-acetylcysteine.

PURPOSE: To compare physiological responses to submaximal cycling and sprint cycling performance in women using oral contraceptives (WomenOC) and naturally cycling women (WomenNC) and to determine whether N-acetylcysteine (NAC) supplementation mediates these responses. METHODS: Twenty recreationally trained women completed five exercise trials (i.e., an incremental cycling test, a familiarisation trial, a baseline performance trial and two double-blind crossover intervention trials). During the intervention trials participants supplemented with NAC or a placebo 1 h before exercise. Cardiopulmonary parameters and blood biochemistry were assessed during 40 min of fixed-intensity cycling at 105% of gas-exchange threshold and after 1-km cycling time-trial. RESULTS: WomenOC had higher ventilation (ß [95% CI] = 0.07 L·min-1 [0.01, 0.14]), malondialdehydes (ß = 12.00 mmol·L-1 [6.82, 17.17]) and C-reactive protein (1.53 mg·L-1 [0.76, 2.30]), whereas glutathione peroxidase was lower (ß =  22.62 mU·mL-1 [- 41.32, - 3.91]) compared to WomenNC during fixed-intensity cycling. Plasma thiols were higher at all timepoints after NAC ingestion compared to placebo, irrespective of group (all p < 0.001; d = 1.45 to 2.34). For WomenNC but not WomenOC, the exercise-induced increase in malondialdehyde observed in the placebo trial was blunted after NAC ingestion, with lower values at 40 min (p = 0.018; d = 0.73). NAC did not affect cycling time-trial performance. CONCLUSIONS: Blood biomarkers relating to oxidative stress and inflammation are elevated in WomenOC during exercise. There may be an increased strain on the endogenous antioxidant system during exercise, since NAC supplementation in WomenOC did not dampen the exercise-induced increase in malondialdehyde. Future investigations should explore the impact of elevated oxidative stress on exercise adaptations or recovery from exercise in WomenOC.

Mesenchymal Stem/Stromal Cells and Their Role in Oxidative Stress Associated with Preeclampsia.

Preeclampsia (PE) is a serious medically important disorder of human pregnancy, which features de novo pregnancy-induced hypertension and proteinuria. The severe form of PE can progress to eclampsia, a convulsive, life-threatening condition. When placental growth and perfusion are abnormal, the placenta experiences oxidative stress and subsequently secretes abnormal amounts of certain pro-angiogenic factors (eg, PlGF) as well as anti-angiogenic factors (eg, sFlt-1) that enter the maternal circulation. The net effect is damage to the maternal vascular endothelium, which subsequently manifests as the clinical features of PE. Other than delivery of the fetus and placenta, curative treatments for PE have not yet been forthcoming, which reflects the complexity of the clinical syndrome. A major source of reactive oxygen species that contributes to the widespread maternal vascular endothelium damage is the PE-affected decidua. The role of decidua-derived mesenchymal stem/stromal cells (MSC) in normotensive and pathological placenta development is poorly understood. The ability to respond to an environment of oxidative damage is a "universal property" of MSC but the biological mechanisms that MSC employ in response to oxidative stress are compromised in PE. In this review, we discuss how MSC respond to oxidative stress in normotensive and pathological conditions. We also consider the possibility of manipulating the oxidative stress response of abnormal MSC as a therapeutic strategy to treat preeclampsia.

Selenium Deficiency during Pregnancy in Mice Impairs Exercise Performance and Metabolic Function in Adult Offspring.

Selenium deficiency during the perinatal period programs metabolic dysfunction in offspring. Postnatal exercise may prevent the development of programmed metabolic disease. This study investigated the impact of selenium deficiency on offspring exercise behavior and whether this improved metabolic health. Female C57BL/6 mice were randomly allocated to control (NormalSe, >190 µg/Se/kg, n = 8) or low-selenium (LowSe, <50 µg/Se/kg, n = 8) diets from four weeks before mating. Male offspring were weaned at postnatal day (PN) twenty-four and placed on a normal chow diet. At PN60, mice were placed in cages with bi-directional running wheels and monitored until PN180. LowSe offspring had a reduced average weekly running speed and distance (p < 0.05). LowSe offspring exhibited glucose intolerance, with increased peak blood glucose (p < 0.05) and area under the curve following an intra-peritoneal injection of glucose (p < 0.05). Furthermore, mRNA expression of several selenoproteins within cardiac and skeletal muscle were increased in LowSe offspring (p < 0.05). The results indicated that selenium deficiency during development reduces exercise behavior. Furthermore, exercise does not prevent programmed glucose intolerance in low-selenium offspring. This highlights that exercise may not be the optimal intervention for metabolic disease in offspring impacted by selenium deficiency in early life.

Selenoproteins in the Human Placenta: How Essential Is Selenium to a Healthy Start to Life?

Selenium is an essential trace element required for human health, and selenium deficiency has been associated with many diseases. The daily recommended intake of selenium is 60 µg/day for adults, which increases to 65 µg/day for women when pregnant. Selenium is incorporated into the 21st amino acid, selenocysteine (sec), a critical component of selenoproteins that plays an important role in a variety of biological responses such as antioxidant defence, reactive oxygen species (ROS) signalling, formation of thyroid hormones, DNA synthesis and the unfolded protein response in the endoplasmic reticulum (ER). Although 25 selenoproteins have been identified, the role of many of these is yet to be fully characterised. This review summarises the current evidence demonstrating that selenium is essential for a healthy pregnancy and that poor selenium status leads to gestational disorders. In particular, we focus on the importance of the placental selenoproteome, and the role these proteins may play in a healthy start to life.

The effect of gestational age on mitochondrial properties of the mouse placenta.

Mitochondria are organelles within the cell that generate energy, which is essential to the developing placenta. As the placenta approaches term, organelles such as mitochondria and the endoplasmic reticulum adapt to cellular stressors (e.g. oxidative stress and fluctuations in oxygen concentration) which are likely to result in the progressive decline of tissue function, known as placental ageing. This ageing phenotype may induce cellular senescence, a process whereby the cell is no longer proliferating, yet remains metabolically active. Mitochondria, endoplasmic reticulum and senescent processes are still poorly understood in the developing placenta. Therefore, a rodent ontogeny model was used to measure genes and proteins involved in mitochondrial biogenesis, antioxidant function, electron transport chain, mitophagy, dynamics and unfolded protein response in the placenta. CD-1 mouse placental samples were collected at embryonic day (E)12.5, E14.5, E16.5 and E18.5 of pregnancy for gene and protein analysis via qPCR, protein assays and Western blotting. Mitochondrial content, SDHB (complex II) and MFN2 (mitochondrial fusion) proteins were all increased throughout pregnancy, while citrate synthase activity/mitochondrial content, Tfam, Sirt3, Mfn1, TOMM20 (mitochondrial biogenesis and dynamics); Tp53(senescence); Eif2ak3, Eif4g1(endoplasmic reticulum stress);NDUFB8, UQCRC2, ATP5A (electron transport chain sub-complexes) were decreased at E18.5, compared to E12.5. Overall, mitochondria undergo changes in response to gestational progression and pathways associated with cellular ageing to facilitate adaptions in a healthy pregnancy. This data holds great promise that mitochondrial markers across pregnancy may help to establish when a placenta is ageing inappropriately. Lay summary: Human pregnancy lasts approximately 266 days. If a baby is born early, organs may be poorly formed but if pregnancy continues past this time, stillbirth risk is increased. Gestational duration is regulated by the placenta. As the placenta approaches the end of pregnancy, it displays properties similar to tissues from aged individuals. However, it is unknown how this placental ageing contributes to pregnancy duration. This study characterised normal placental ageing by measuring properties of mitochondria in healthy placentas collected at four different gestational ages ranging from 7 days before birth to 1 day before birth of the 19-day mouse pregnancy. We found that mitochondrial number increased per cell but that a marker of mitochondrial function was reduced. Proteins that control mitochondrial number, morphology and function also changed over time. This work lays the platform to understand how placental ageing contributes to adverse pregnancy outcomes related to altered pregnancy duration.

A Novel Ferritin-Core Analog Is a Safe and Effective Alternative to Oral Ferrous Iron for Treating Iron Deficiency during Pregnancy in Mice.

BACKGROUND: Many women enter pregnancy with iron stores that are insufficient to maintain maternal iron balance and support fetal development and consequently, often require iron supplements. However, the side effects associated with many currently available iron supplements can limit compliance. OBJECTIVE: This study aimed to test the safety and efficacy of a novel nanoparticulate iron supplement, a dietary ferritin analog termed iron hydroxide adipate tartrate (IHAT), in pregnant mice. METHODS: Female C57BL/6 mice were maintained on either an iron-deficient or a control diet for 2 wk prior to timed mating to develop iron-deficient or iron-sufficient pregnancy models, respectively. Mice from each model were then gavaged daily with 10 mg iron/kg body weight as either IHAT or ferrous sulfate, or with water only, beginning on embryonic day (E) 4.5. Mice were killed on E18.5 and maternal iron and hematological parameters were measured. The expression of genes encoding iron transporters and oxidative stress markers in the duodenum and placenta were determined, along with hepatic expression of the gene encoding the iron regulatory hormone hepcidin and fetal iron. RESULTS: Oral IHAT and ferrous sulfate were equally effective at increasing maternal hemoglobin (20.2% and 16.9%, respectively) and hepatic iron (30.2% and 29.3%, respectively), as well as total fetal iron (99.7% and 83.8%, respectively), in iron-deficient pregnant mice compared with those gavaged with water only, with no change in oxidative stress markers seen with either treatment. However, there was a significant increase in the placental expression of the oxidative stress marker heme oxygenase 1 in iron-replete pregnant mice treated with ferrous sulfate when compared with iron-replete pregnant mice gavaged with IHAT (96.9%, P <0.05). CONCLUSIONS: IHAT has proved a safe and effective alternative to oral ferrous sulfate in mice, and it has potential for treating iron deficiency in human pregnancy.

Maternal diet high in linoleic acid alters offspring fatty acids and cardiovascular function in a rat model.

Linoleic acid (LA), an essential n-6 fatty acid (FA), is critical for fetal development. We investigated the effects of maternal high LA (HLA) diet on offspring cardiac development and its relationship to circulating FA and cardiovascular function in adolescent offspring, and the ability of the postnatal diet to reverse any adverse effects. Female Wistar Kyoto rats were fed low LA (LLA; 1·44 % energy from LA) or high LA (HLA; 6·21 % energy from LA) diets for 10 weeks before pregnancy and during gestation/lactation. Offspring, weaned at postnatal day 25, were fed LLA or HLA diets and euthanised at postnatal day 40 (n 6-8). Maternal HLA diet decreased circulating total cholesterol and HDL-cholesterol in females and decreased total plasma n-3 FA in males, while maternal and postnatal HLA diets decreased total plasma n-3 FA in females. α-Linolenic acid (ALA) and EPA were decreased by postnatal but not maternal HLA diets in both sexes. Maternal and postnatal HLA diets increased total plasma n-6 and LA, and a maternal HLA diet increased circulating leptin, in both male and female offspring. Maternal HLA decreased slopes of systolic and diastolic pressure-volume relationship (PVR), and increased cardiac Col1a1, Col3a1, Atp2a1 and Notch1 in males. Maternal and postnatal HLA diets left-shifted the diastolic PVR in female offspring. Coronary reactivity was altered in females, with differential effects on flow repayment after occlusion. Thus, maternal HLA diets impact lipids, FA and cardiac function in offspring, with postnatal diet modifying FA and cardiac function in the female offspring.

Nutritional properties of selected superfood extracts and their potential health benefits.

BACKGROUND: The term 'superfoods' is used to market foods considered to have significant health benefits. 'Superfoods' are claimed to prevent diseases as well as improving overall health, though the lack of explicit criteria means that any food can be labelled 'super' without support from scientific research. Typically, these 'superfoods' are rich in a particular nutrient for example antioxidants or omega-3 fatty acids. The objective of this study was to investigate the nutritional properties of a selection of superfood seeds: flax, chia, hulled sunflower and two types of processed hemp seeds and determine whether they may have potential health benefits. METHODS: We developed a simple aqueous extraction method for ground seeds and analysed their composition by mineral, protein and monosaccharide analyses. Cell viability assays were performed on Caco-2 and IEC-6 intestinal epithelial cells using increasing doses of the prepared extracts. RESULTS: Increased cell viability was observed in both cell lines with increasing concentrations of the flax seed, chia seed or hulled sunflower extracts (P < 0.05). Compositional analyses revealed the presence of polysaccharides, proteins and essential minerals in the aqueous extracts and in vitro assays showed sunflower had the highest antioxidant activity. However, differences in extract composition and antioxidant properties could not be directly related to the observed increase in cell viability suggesting that other components in the extracts may be responsible. Future studies will further characterize these extracts and investigate whether they are beneficial for gastrointestinal health.

Sex-Specific Differences in Lysine, 3-Hydroxybutyric Acid and Acetic Acid in Offspring Exposed to Maternal and Postnatal High Linoleic Acid Diet, Independent of Diet.

BACKGROUND: Linoleic acid (LA) is an essential polyunsaturated fatty acid (PUFA) that is required for foetal growth and development. Excess intake of LA can be detrimental for metabolic health due to its pro-inflammatory properties; however, the effect of a diet high in LA on offspring metabolites is unknown. In this study, we aimed to determine the role of maternal or postnatal high linoleic acid (HLA) diet on plasma metabolites in adult offspring. METHODS: Female Wistar Kyoto (WKY) rats were fed with either low LA (LLA) or HLA diet for 10 weeks prior to conception and during gestation/lactation. Offspring were weaned at postnatal day 25 (PN25), treated with either LLA or HLA diets and sacrificed at PN180. Metabolite analysis was performed in plasma samples using Nuclear Magnetic Resonance. RESULTS: Maternal and postnatal HLA diet did not alter plasma metabolites in male and female adult offspring. There was no specific clustering among different treatment groups as demonstrated by principal component analysis. Interestingly, there was clustering among male and female offspring independent of maternal and postnatal dietary intervention. Lysine was higher in female offspring, while 3-hydroxybutyric acid and acetic acid were significantly higher in male offspring. CONCLUSION: In summary, maternal or postnatal HLA diet did not alter the plasma metabolites in the adult rat offspring; however, differences in metabolites between male and female offspring occurred independently of dietary intervention.

Circulating trace elements for the prediction of preeclampsia and small for gestational age babies.

INTRODUCTION: Poor gestational outcomes due to placental insufficiency can have lifelong consequences for mother and child. OBJECTIVE: There is a need for better methods of diagnosis, and elemental metabolomics may provide a means to determine the risk of gestational disorders. METHODS: This study used blood plasma samples collected at 36 weeks' gestation from women who later developed preeclampsia (n = 38), or small-for-gestational age babies (n = 91), along with matched controls (n = 193). Multi-element analysis was conducted by inductively coupled plasma mass spectrometer (ICP-MS), allowing simultaneous measurement of 28 elements. RESULTS: Women who later developed PE, exhibited significantly increased concentrations of K, Rb and Ba. For SGA pregnancies, there was a significant increase in Cu and a decrease in As concentrations. Despite significant differences in single elements, the elemental profile of groups indicated no clustering of control, PE, or SGA samples. Positive predicative values correctly identified approximately 60% of SGA and 70% of PE samples. CONCLUSION: This is the first-time elemental metabolomics has been used to predict SGA and PE at 36 weeks. Though significant changes were identified, routine clinical use may be limited but may contribute to a multi marker test. Future analysis should include other biomarkers, metabolic data or clinical measurements made throughout gestation.

Analysis of mitochondrial regulatory transcripts in publicly available datasets with validation in placentae from pre-term, post-term and fetal growth restriction pregnancies.

INTRODUCTION: The human placenta has a defined lifespan and placental aging is a key feature as pregnancy progresses. Placental aging and mitochondrial dysfunction are known to play a key role in pregnancy pathophysiology. Premature aging of the placenta has also been linked with placental dysfunction resulting in poor fetal development and premature birth. METHODS: The expression of key mitochondrial-related genes were analysed in a series of publicly available databases then expression changes were validated in placental samples collected from term, pre-term, post-term pregnancies and pregnancies complicated by fetal growth restriction (FGR). Gene and protein expression levels of MFN1, MFN2, TFAM, TOMM20, OPA3 and SIRT4 were measured in placental tissues via qPCR and western blotting. RESULTS: Initial analysis found that key mitochondrial transcripts related to biogenesis, bioenergetics and mitophagy clustered by pregnancy trimester. A refined list of 13 mitochondrial-related genes were investigated in additional external datasets of pregnancy complications. In the new cohort, protein expression of MFN1 was decreased in FGR and MFN2 is decreased in post-term placenta. Analysis of placental tissues revealed that TOMM20 gene and protein expression was altered in FGR and post-term placenta. DISCUSSION: MFN1 and MFN2 play a major role in mitochondrial dynamics, and alterations in these markers have been highlighted in early unexplained miscarriage. TOMM20 is an importer protein that plays a major role in mitophagy and changes have also been identified in age-related diseases. Significant changes in MFN1, MFN2 and TOMM20 indicate that mitochondrial regulators play a critical role in placental aging and placental pathophysiology.

The Placental Ferroxidase Zyklopen Is Not Essential for Iron Transport to the Fetus in Mice.

BACKGROUND: The ferroxidase zyklopen (Zp) has been implicated in the placental transfer of iron to the fetus. However, the evidence for this is largely circumstantial. OBJECTIVES: This study aimed to determine whether Zp is essential for placental iron transfer. METHODS: A model was established using 8- to 12-wk-old pregnant C57BL/6 mice on standard rodent chow in which Zp was knocked out in the fetus and fetal components of the placenta. Zp was also disrupted in the entire placenta using global Zp knockout mice. Inductively coupled plasma MS was used to measure total fetal iron, an indicator of the amount of iron transferred by the placenta to the fetus, at embryonic day 18.5 of gestation. Iron transporter expression in the placenta was measured by Western blotting, and the expression of Hamp1, the gene encoding the iron regulatory hormone hepcidin, was determined in fetal liver by real-time PCR. RESULTS: There was no change in the amount of iron transferred to the fetus when Zp was disrupted in either the fetal component of the placenta or the entire placenta. No compensatory changes in the expression of the iron transport proteins transferrin receptor 1 or ferroportin were observed, nor was there any change in fetal liver Hamp1 mRNA. Hephl1, the gene encoding Zp, was expressed mainly in the maternal decidua of the placenta and not in the nutrient-transporting syncytiotrophoblast. Disruption of Zp in the whole placenta resulted in a 26% increase in placental size (P < 0.01). CONCLUSIONS: Our data indicate that Zp is not essential for the efficient transfer of iron to the fetus in mice and is localized predominantly in the maternal decidua. The increase in placental size observed when Zp is knocked out in the entire placenta suggests that this protein may play a role in placental development.