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.

Does the radical GPRI strongly depend on the population scheme? A comparative study to predict radical attack on unsaturated molecules with the radical general-purpose reactivity indicator.

The reactivity of 22 unsaturated molecules undergoing attack by a methyl radical (⋅CH3) have been elucidated using the condensed radical general-purpose reactivity indicator (condensed radical GPRI) appropriate for relatively nucleophilic or electrophilic molecules. Using the appropriate radical GPRI equation for electrophilic attack or nucleophilic radical attack, seven different population schemes were used to assign the most reactive atoms in each of the 22 molecules. The results show that the condensed radical GPRI is sensitive to the population scheme chosen, but less sensitive than the radical Fukui function. Therefore, the reliability of these methods depends on the population scheme. Our investigation indicates that the condensed radical GPRI is most accurate in predicting the dominant products of the methyl radical addition reactions on a variety of unsaturated molecules when the Hirshfeld, Merz-Singh-Kollman, or Voronoi deformation density population schemes are used. Furthermore, for all populations schemes in the majority of instances where the radical Fukui function failed the radical GPRI was able to identify the most reactive atom under certain reactivity conditions.

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.

Bioaccumulative chemicals are either too hard or too soft: Conceptual density functional theory as a screening tool for emerging pollutants.

Conceptual density functional theory (CDFT) descriptors were computed to predict the environmental fate of approximately 6,000 widely used industrial chemicals. CDFT descriptors aligned with a molecule's possible bioaccumulation mechanism, i.e., soft chemicals are lipophilic, whereas hard chemicals may bioaccumulate by other mechanisms such as protein binding. The results have provided us with a new "rule of thumb" to guide risk assessment of chemical hazards: suspected persistent organic pollutants are either too hard (η > 0.40 hartree) or too soft (α > 200 Å3). This offers a novel approach to environmental risk assessment using two fundamental properties of a molecule.

Warning! The negative divergence of the stress-tensor does not always yield the Ehrenfest force.

It has been assumed that the negative divergence of all stress tensors in common use yields the same force. This work finds that this is untrue, and, in fact, can vary wildly. We demonstrate this for the hydrogen atom, the one-particle isotropic harmonic oscillator, and a particle in an infinite spherical well where the exact density, pair-density, and the first order reduced density matrix are known for ground and excited states without any approximation. The Ehrenfest stress-tensor is introduced as any stress-tensor whose negative divergence will yield the corresponding Ehrenfest force for the same system when the exact wave-function is utilized. Stress-tensors within the literature are examined to show those that are Ehrenfest stress-tensors. Those that differ are demonstrated by how they differ within an exact formulation. The proof that the negative divergence of an Ehrenfest stress-tensor yields the Ehrenfest force is summarized.

An information-theoretic approach to basis-set fitting of electron densities and other non-negative functions.

The numerical ill-conditioning associated with approximating an electron density with a convex sum of Gaussian or Slater-type functions is overcome by using the (extended) Kullback-Leibler divergence to measure the deviation between the target and approximate density. The optimized densities are non-negative and normalized, and they are accurate enough to be used in applications related to molecular similarity, the topology of the electron density, and numerical molecular integration. This robust, efficient, and general approach can be used to fit any non-negative normalized functions (e.g., the kinetic energy density and molecular electron density) to a convex sum of non-negative basis functions. We present a fixed-point iteration method for optimizing the Kullback-Leibler divergence and compare it to conventional gradient-based optimization methods. These algorithms are released through the free and open-source BFit package, which also includes a L2-norm squared optimization routine applicable to any square-integrable scalar function.

Maternal hypothyroidism in rats impairs placental nutrient transporter expression, increases labyrinth zone size, and impairs fetal growth.

INTRODUCTION: Hypothyroidism during pregnancy is associated with fetal growth restriction (FGR). FGR is commonly caused by placental insufficiency and yet the role of hypothyroidism in placental regulation of fetal growth is unknown. This study aimed to investigate the effects of maternal hypothyroidism on placental nutrient transporter expression, placental morphology, and placental metabolism. METHODS: Hypothyroidism was induced in female Sprague-Dawley rats by adding methimazole (MMI) to drinking water at moderate (MOD, MMI at 0.005% w/v) and severe (SEV, MMI at 0.02% w/v) doses from one week prior to pregnancy and throughout gestation. Maternal and fetal tissues were collected on embryonic day 20 (E20). RESULTS: Hypothyroidism reduced fetal weight (PTrt<0.001) despite causing fetal hyperglycaemia (PTrt = 0.016). Placental weight was not affected by hypothyroidism however placental efficiency was reduced (PTrt<0.001), as was the junctional zone (JZ):labyrinth zone (LZ) weight ratio (PTrt = 0.005). LZ glycogen content was increased (PTrt = 0.029) and while mRNA expression of glucose transporters was reduced by hypothyroidism, only GLUT1 protein expression was reduced in male LZs. Maternal hypothyroidism reduced mitochondrial content (PTrt = 0.031), particularly in SEV males relative to CON males (P = 0.004). Protein expression of Complex V (P < 0.001) and Complex III (P = 0.002) of the electron transport chain were also reduced in males. Maternal hypothyroidism reduced LZ (PTrt<0.001) and fetal plasma triglycerides (P = 0.019) while fetal free fatty acids and the expression of LZ lipid transporters was not affected. DISCUSSION: Overall, maternal hypothyroidism may lead to FGR through reduced maternal T4 availability, changes to placental morphology, altered nutrient transporter expression and sex-specific effects on placental metabolism. Changes to LZ glycogen and triglyceride stores as well as mitochondrial content suggest a metabolic shift from oxidative phosphorylation to anaerobic glycolysis in males. These changes also likely impact fetal substrate availability and therefore fetal growth.

The role of maternal choline, folate and one-carbon metabolism in mediating the impact of prenatal alcohol exposure on placental and fetal development.

Prenatal alcohol consumption (PAE) may be associated with a broad spectrum of impacts, ranging from no overt effects, to miscarriage, fetal growth restriction and fetal alcohol spectrum disorder. A major mechanism underlying the effects of PAE is considered to be altered DNA methylation and gene expression. Maternal nutritional status may be an important factor in determining the extent to which PAE impacts pregnancy outcomes, particularly the dietary micronutrients folate and choline because they provide methyl groups for DNA methylation via one carbon metabolism. This review summarises the roles of folate and choline in development of the blastocyst, the placenta and the fetal brain, and examines the evidence that maternal intake of these micronutrients can modify the effects of PAE on development. Studies of folate or choline deficiency have found reduced blastocyst development and implantation, reduced placental invasion, vascularisation and nutrient transport capability, impaired fetal brain development, and abnormal neurodevelopmental outcomes. PAE has been shown to reduce absorption and/or metabolism of folate and choline and to produce similar outcomes to maternal choline/folate deficiency. A few studies have demonstrated that the effects of PAE on brain development can be ameliorated by folate or choline supplementation; however, there is very limited evidence on the effects of supplementation in early pregnancy on the blastocyst and placenta. Further studies are required to support these findings and to determine optimal supplementation parameters.

Vitamin B12 deficiency induces glucose intolerance, delays peak insulin levels and promotes ketogenesis in female rats.

Vitamin B12 (B12) deficiency is common among individuals with diabetes mellitus, but it is unknown if B12 deficiency contributes to impaired glucose homeostasis in this disorder. Female Sprague-Dawley rats were assigned to a control or B12-deficient diet for 4 weeks. Intraperitoneal glucose tolerance tests were performed after 25 days, and blood and liver samples were collected for metabolic profiling. B12 deficiency resulted in a prediabetic-like phenotype characterised by glucose intolerance, a delayed peak in plasma insulin levels following a glucose challenge and increased ketogenesis. We attributed increased ketogenesis to reduced liver anaplerosis, which limited the availability of the TCA cycle intermediates citrate, succinate and succinyl-CoA. This was associated with increased Mut mRNA levels and citrate synthase activity in the liver. One-carbon metabolite levels were altered in plasma and the liver, which was linked to reduced methylation capacity, altered amino acid levels and elevated Slc7a5 mRNA expression. Plasma folate and biotin levels were reduced, as were the majority of B vitamins in the liver. Changes in these B12-dependent processes and reduced B vitamin amounts likely contributed to deficits in glucose handling. Our findings highlight that B12 deficiency may promote the development of metabolic disorders like diabetes mellitus and emphasise the importance of adequate B12 intake for metabolic health.

Prenatal Choline Supplementation Alters One Carbon Metabolites in a Rat Model of Periconceptional Alcohol Exposure.

Prenatal alcohol exposure disturbs fetal and placental growth and can alter DNA methylation (DNAm). Supplementation with the methyl donor choline can increase fetal and placental growth and restore DNAm, suggesting converging effects on one-carbon metabolism (1CM). We investigated the impact of periconceptional ethanol (PCE) exposure and prenatal choline supplementation on 1CM in maternal, placental, and fetal compartments. Female Sprague Dawley rats were given a liquid diet containing 12.5% ethanol (PCE) or 0% ethanol (control) for 4 days before and 4 days after conception. Dams were then placed on chow with different concentrations of choline (1.6 g, 2.6 g, or 7.2 g choline/kg chow). Plasma and tissues were collected in late gestation for the analysis of 1CM components by means of mass spectrometry and real-time PCR. PCE reduced placental components of 1CM, particularly those relating to folate metabolism, resulting in a 3−7.5-fold reduction in the ratio of s-adenosylmethionine:s-adenosylhomocysteine (SAM:SAH) (p < 0.0001). Choline supplementation increased placental 1CM components and the SAM:SAH ratio (3.5−14.5-fold, p < 0.0001). In the maternal and fetal compartments, PCE had little effect, whereas choline increased components of 1CM. This suggests that PCE impairs fetal development via altered placental 1CM, highlighting its role in modulating nutritional inputs to optimize fetal development.

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.

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.

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.

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.

Developmental Vitamin D Deficiency in Pregnant Rats Does Not Induce Preeclampsia.

Preeclampsia is a pregnancy disorder characterized by hypertension. Epidemiological studies have associated preeclampsia with an increased risk of neurodevelopmental disorders in offspring, such as autism and schizophrenia. Preeclampsia has also been linked with maternal vitamin D deficiency, another candidate risk factor also associated with autism. Our laboratory has established a gestational vitamin-D-deficient rat model that shows consistent and robust behavioural phenotypes associated with autism- and schizophrenia-related animal models. Therefore, we explored here whether this model also produces preeclampsia as a possible mediator of behavioural phenotypes in offspring. We showed that gestational vitamin D deficiency was not associated with maternal blood pressure or proteinuria during late gestation. Maternal and placental angiogenic and vasculogenic factors were also not affected by a vitamin-D-deficient diet. We further showed that exposure to low vitamin D levels did not expose the placenta to oxidative stress. Overall, gestational vitamin D deficiency in our rat model was not associated with preeclampsia-related features, suggesting that well-described behavioural phenotypes in offspring born to vitamin-D-deficient rat dams are unlikely to be mediated via a preeclampsia-related mechanism.

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.

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.

Let's Talk about Placental Sex, Baby: Understanding Mechanisms That Drive Female- and Male-Specific Fetal Growth and Developmental Outcomes.

It is well understood that sex differences exist between females and males even before they are born. These sex-dependent differences may contribute to altered growth and developmental outcomes for the fetus. Based on our initial observations in the human placenta, we hypothesised that the male prioritises growth pathways in order to maximise growth through to adulthood, thereby ensuring the greatest chance of reproductive success. However, this male-specific "evolutionary advantage" likely contributes to males being less adaptable to shifts in the in-utero environment, which then places them at a greater risk for intrauterine morbidities or mortality. Comparatively, females are more adaptable to changes in the in-utero environment at the cost of growth, which may reduce their risk of poor perinatal outcomes. The mechanisms that drive these sex-specific adaptations to a change in the in-utero environment remain unclear, but an increasing body of evidence within the field of developmental biology would suggest that alterations to placental function, as well as the feto-placental hormonal milieu, is an important contributing factor. Herein, we have addressed the current knowledge regarding sex-specific intrauterine growth differences and have examined how certain pregnancy complications may alter these female- and male-specific adaptations.

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.

Is the link between elevated TSH and gestational diabetes mellitus dependant on diagnostic criteria and thyroid antibody status: a systematic review and meta-analysis.

PURPOSE: Clinical studies have investigated the prevalence of gestational diabetes mellitus (GDM) in women with subclinical hypothyroidism (SCH). While some studies demonstrate a clear association, others do not. It is possible this may be due to varied diagnostic criteria for SCH and the presence of thyroid antibodies (TA). We conducted a meta-analysis, separating patients diagnosed with SCH using a diagnostic cut-off <4.0 mIU/L from those diagnosed using a cut-off >4.0 mIU/L and determined the association with GDM and factored TA status into our analysis. METHODS: A computerised search of five databases including PubMed, Embase, Cochrane Library, Web of Science and CINAHL returned 787 records. Two independent reviewers assessed abstracts and full texts against pre-specified inclusion and exclusion criteria. Ten cohort studies were included in the final analysis. The diagnostic criteria for SCH and incidence of GDM were extracted from each study. Study quality and risk of bias was assessed by two reviewers. RESULTS: TSH levels <4.0 mIU/L for SCH diagnosis was not associated with GDM unless patients were TA positive. Studies that used a diagnostic cut-off >4.0 mIU/L saw a significant increase in the odds of GDM, regardless of TA status (OR = 1.60, 95% CI 1.33-1.93). CONCLUSIONS: Women with TSH levels >4.0 mIU/L have an increased odds of GDM regardless of TA status but at TSH levels <4.0 mIU/L, GDM is dependent on TA status. The use of TSH levels to identify pregnancies at risk of GDM is a novel concept that warrants exploration.