Placental Metabolism Research Articles

L-ergothioneine reduces mitochondrial-driven NLRP3 activation in gestational diabetes mellitus

BackgroundMaternal hyperglycaemia has a significant impact on placental metabolism and mitochondrial function. The NLRP3 inflammasome is responsive to endogenous signals of mitochondrial dysfunction. We tested our hypothesis that mitochondrial dysfunction orchestrates activation of the NLRP3 inflammasome and contributes to inflammation in gestational diabetes mellitus (GDM). MethodsFasting blood, omental and placental tissue were collected on the day of caesarean section from nulliparous women with normal glucose tolerant (NGT) (n = 30) and GDM (n = 27) pregnancies. Cell-free mitochondrial DNA (cf-mtDNA) copy number was quantified by real-time PCR. M1-like (CD14+CD86+CD206-) and M2-like (CD14+CD86+CD206+) macrophage populations were characterized by flow cytometry. Immunoblotting for protein expression of NLRP3, ASC and caspase-1 was performed in maternal BMI and age-matched tissue samples. IL-1β and IL-18 were measured by multiplex ELISA. Placental explants from GDM participants were cultured for 24 h with 1 mM L-ergothioneine (antioxidant) and 1 µM MCC950 (NLRP3 inhibitor). ResultsCf-mtDNA copy numbers were significantly higher in GDM compared to NGT participants (p = 0.002). Placental populations of CD14+ (p = 0.02) and CD14+CD86+CD206- (p = 0.03) macrophages produced significantly increased levels of mitochondrial superoxide in GDM compared to NGT participants. Placental production of IL-18 (p = 0.04) was significantly increased in GDM. This increase in placental IL-18 was attenuated by treatment with 1 µM MCC950 (p = 0.0005), and 1 mM L-ergothioneine (p = 0.007). ConclusionPlacental inflammation is significantly increased in women with GDM. Furthermore, this increase may be initiated by elevated production of mitochondrial superoxide by macrophage subpopulations and orchestrated by the NLRP3 inflammasome. The mitochondrial antioxidant, L-ergothioneine, ameliorates NLRP3-induced placental inflammation in GDM, identifying a potential therapeutic role.

Lachnospiraceae-derived butyrate mediates protection of high fermentable fiber against placental inflammation in gestational diabetes mellitus.

Inflammation-associated insulin resistance is a key trigger of gestational diabetes mellitus (GDM), but the underlying mechanisms and effective interventions remain unclear. Here, we report the association of placental inflammation (tumor necrosis factor-α) and abnormal maternal glucose metabolism in patients with GDM, and a high fermentable dietary fiber (HFDF; konjac) could reduce GDM development through gut flora-short-chain fatty acid-placental inflammation axis in GDM mouse model. Mechanistically, HFDF increases abundances of Lachnospiraceae and butyrate, reduces placental-derived inflammation by enhancing gut barrier and inhibiting the transfer of bacterial-derived lipopolysaccharide, and ultimately resists high-fat diet-induced insulin resistance. Lachnospiraceae and butyrate have similar anti-GDM and anti-placental inflammation effects, and they can ameliorate placental function and pregnancy outcome effects probably by dampening placental immune dysfunction. These findings demonstrate the involvement of important placental inflammation-related mechanisms in the progression of GDM and the great potential of HFDFs to reduce susceptibility to GDM through gut-flora-placenta axis.

Maternal body mass index, birthweight, and placental glucose metabolism: evidence for a role of placental hexokinase

BackgroundThe principal fetal energy source is glucose provided by placental transfer of maternal glucose. However, the placenta’s glucose consumption exhibits considerable variation. Hexokinase is the first and one of the rate-limiting enzymes of glycolysis that phosphorylates glucose to glucose 6-phosphate. The role of placental hexokinase activity in human placental glucose metabolism is unknown. ObjectivesTo test the hypothesis that placental hexokinase activity is related to maternal body mass index, placental glucose uptake and consumption, and birth weight. Study designSixty-seven healthy pregnant participants at term were included in this study at Oslo University Hospital, Norway. Placental hexokinase activity was measured by using a colorimetric assay. The mass of glucose taken up by the uteroplacental unit and the fetus was obtained by measuring arterio-venous glucose differences combined with Doppler assessment of uterine and umbilical blood flow. Blood samples were obtained from the maternal radial artery, uterine vein, and umbilical artery and vein. The uteroplacental glucose consumption constituted the difference between uteroplacental and fetal glucose uptake. Spearman’s rank correlation was performed for statistical analyses to study the correlation of placental hexokinase activity (mU/mg protein) with prepregnancy body mass index, maternal glucose and insulin, birth weight, uteroplacental glucose uptake and consumption, and fetal glucose uptake (μmol/min). Partial rank correlation analysis was performed when controlling for hours of fasting or placental weight. ResultsHexokinase activity was detectable in all placental tissue samples. Mean (SD) activity was 19.6 (4.64) mU/mg of protein. Placental hexokinase activity correlated positively with prepregnancy body mass index (Spearman’s rho (ρ)=0.33; P=0.006). Upon controlling for hours of fasting, hexokinase activity showed positive correlations with both maternal glucose (r=0.30; P=0.01) and insulin (r=0.28; P=0.02). Hexokinase activity was positively correlated with uteroplacental glucose uptake (ρ=0.31; P=0.01) and consumption (ρ=0.28; P=0.02). Hexokinase activity did not correlate with fetal glucose uptake. Upon controlling for placental weight, hexokinase activity showed a positive correlation with birth weight (r=0.31; P=0.01). ConclusionOur findings suggest that placental hexokinase, being crucial for uteroplacental retention of glucose for own disposition, is related to both maternal body mass index and birth weight independent of placental weight. Placental hexokinase may play a central role in the relationship between maternal glucose dysregulation and fetal growth. Thus, the current study supports the need to develop clinically useful tools to assess the metabolic properties of the placenta.

Nobiletin inhibits hypoxia-induced placental redox imbalance and subsequent offspring brain damage by regulating the one-carbon metabolism

Nobiletin (NOB) is one of the major polymethoxyflavone in citrus peels, which has antioxidant activities. The purpose of this study was to investigate the effects of NOB on hypoxia-induced placental oxidative stress and its mechanism. In vitro experiments, JEG-3 hypoxic model was constructed, and treated with 100 μM NOB. In vivo experiment, pregnant rats were injected intraperitoneally with 50 mg/kg body weight NOB daily, and the placental hypoxia model was established by RUPP. NOB hampered the reducing of reducing power in hypoxic cells, promoted NADPH to provide hydrogen donors to regenerate antioxidants GPX and GSH, thereby promoting the decomposition of ROS. NOB alleviated the adverse reaction of hypoxic placental one-carbon metabolism disorder by regulating the levels of homocysteine, DNMTs and TETs. Moreover, NOB suppressed offspring brain damage induced by RUPP. Taken together, NOB attenuated hypoxia-induced placental redox perturbation and subsequent offspring brain injury by modulating one-carbon metabolism.

12 Amino Acid Nutrition in Dairy Cattle: Beyond Milk Protein

Abstract The transition from gestation to lactation, also known as the transition period, is a critical time for dairy cows. This phase is typically defined as 3 weeks before parturition through 3 weeks after parturition. Peak disease incidence (shortly after parturition) corresponds with the time of greatest negative energy balance (NEB) and negative protein balance (NPB), the peak in blood concentrations of nonesterified fatty acids, and the greatest acceleration of milk yield. Decreased fertility in the face of increasing milk production may be attributable to greater severity of postpartum NEB and NPB resulting from inadequate transition management or increased disease rates. The depth and duration of NEB and NPB are highly related to dry matter intake. Formulating and delivering appropriate diets that limit total energy intake to requirements but also provide proper intakes of all other nutrients [including the indispensable amino acids (IAA) Met and Lys] before calving can help lessen the extent of NEB and NPB after calving. Supplementation of rumen-protected methionine (RPM) during the transition period improved uterine immune function through improved glandular morphology, increased neutrophil infiltration after calving, and discovery of neutrophil extracellular trap formation in bovine endometrial tissue. Its supplementation has been reported to reduce the incidence of health complications, better lactation performance, and more favorable biomarker and plasma AA profiles, common in cows with increased liver functionality index. Cows supplemented with rumen-protected lysine (RPL) had decreased liver oxidative stress (SOD1, superoxide dismutase 1) and acute phase response (SAA3, serum amyloid A3) and reduced gene expression of NFKB1 (nuclear factor kappa B1) leading to increased proinflammatory IL1B postpartum, likely indicating improved immune activation when cows consumed RPL, a necessary component of early postpartum health. Our group has reported that a prepartum supply of RPL altered uteroplacental metabolism and glucose transport. This was demonstrated through increased expression of uterine transcripts involved in energy metabolism (GLUT3, glucose transporter 3; PCK1, phosphoenolpyruvate carboxykinase 1) and placental metabolism (FGF2, fibroblast growth factor 2; FGF2R, fibroblast growth factor 2 receptor; and PGF, placental growth factor). We also have demonstrated that RPL prepartum increased the placental protein abundance of FGF2 and LRP1 (low-density lipoprotein receptor-related protein 1), indicating possible enhanced placental metabolic activity, probably linked to trophoblast proliferation and migration processes. Finally, calves from dams fed RPL prepartum had improved overall growth and intake than calves from dams not receiving RPL. In conclusion, providing RPM and RPL during the transition period impacts dairy cows' health, uterine environment, and offspring.

Identifying placental metabolic biomarkers of preterm birth using nuclear magnetic resonance of intact tissue samples

IntroductionOur understanding of the etiology of preterm birth (PTB) is incomplete; however, recent evidence has found a strong association between placental dysfunction and PTB. Altered placental metabolism may precede placental dysfunction and therefore the study of placental metabolic profiles could identify early biomarkers of PTB. In this study, we evaluated the placental metabolome in PTB in intact tissue samples using nuclear magnetic resonance (NMR) and spectral editing. MethodsPlacental tissue samples were collected from nine term pregnancies and nine preterm pregnancies (<37 weeks’ gestation). 1H NMR experiments on unprocessed tissue samples were performed using a high field magnet (500 MHz spectrometer) and a comprehensive multiphase NMR probe. The relative concentrations of 23 metabolites were corrected for gestational age and compared between groups. ResultsThe relative concentration of valine, glutamate and creatine were significantly decreased while alanine, choline and glucose were elevated in placentas from PTB pregnancies compared to controls (p < 0.05). Multivariate analysis using principal component analysis showed the PTB and control groups were significantly separated (p < 0.0001) and pathway analysis identified perturbations in the glycine, serine and threonine metabolism, aminoacyl-tRNA biosynthesis and valine, leucine and isoleucine biosynthesis pathways. ConclusionPTB is associated with significant alterations in placental metabolism. This study helps improve our understanding of the etiology of PTB. It also highlights the potential for small molecule metabolites to serve as placental metabolic biomarkers to aid in the prediction and diagnosis of PTB. The results can be translated to clinical use via in utero magnetic resonance spectroscopy.

FRI492 Malaria In Pregnancy And Lipopolyssacharide Lead To Sex-specific Changes In The Expression Of Genes Involved In The Placental Metabolism Of Thyroid Hormones

Abstract Disclosure: K.N. Fontes: None. V.S. Monteiro: None. C.B. Andrade: None. A.C. Valim: None. V.M. Nascimento: None. D.E. Teixeira: None. A.A. Pinheiro: None. E. Bloise: None. T.M. Ortiga-Carvalho: None. Infection during gestation promotes marked changes in placental physiology, leading to intrauterine growth restriction (IUGR), preterm labor (PTL) and neurodevelopmental disorders. Infection in pregnant women or mice may impact thyroid hormones’ (TH) metabolism and the importance of TH for the development of the placenta and conceptus is widely described in the literature. Our main aim was to evaluate changes in the expression of specific genes involved in placental TH metabolism triggered by malaria in pregnancy (MiP) or bacterial lipopolyssacharide (LPS), in the male and female placenta. Female C57BL/6 mice (8-10 weeks of age) were mated. In the MiP model, dams were infected ip with Plasmodium Berghei ANKA-infected erythrocytes (PBA; 5x105 infected-erythrocytes, n=10) or injected with PBS (contro; n=10) at gestational day (GD)13.5 and sacrificed at GD18.5. In the LPS model, dams were injected ip with LPS (150 µg/kg, n=10) or PBS (control; n=10) at GD17.5 and sacrificed at GD18.5. Maternal blood was collected to evaluate PBA parasitemia. Placental disks were collected from dams delivering at term (GD18.5), and qPCR was performed to evaluate the mRNA expression of genes involved in placental TH metabolism. MiP was confirmed by analysis of parasitemia (15.9%), and resulted in increased maternal spleen weight (P&amp;lt;0.05). As expected, MiP induced PTL (at GD17.5) in 23.1% of dams. Fetal weight and fetal/placental weight ratio were reduced in MiP (at term), compared to control (P&amp;lt;0.05). In the LPS model, 33.3% of dams went into PTL (at GD17.5) and fetal weight was reduced in LPS group (at term), compared to control (P&amp;lt;0.05). In both models, mRNA of the Cxcl1 chemokine (P&amp;lt;0.05) was increased in the male and female placenta at term (P&amp;lt;0.05). Male MiP placentas exhibited a reduction in Slc7a8 (P&amp;lt;0.05) and Dio2 (P&amp;lt;0.05) mRNA expression, whereas female MiP placentas exhibited a reduction in Slc7a8 (P&amp;lt;0.05) and an increase in Slco1c1 and Dio1 (P&amp;lt;0.05) at term. LPS increased Dio1 (P&amp;lt;0.05) mRNA in the male term placenta, and increased Ccl2 (P&amp;lt;0.05) mRNA in the term female placenta. In the present study, MiP was associated with sex-specific changes in the placental expression of TH transporters and deiodinases, while LPS injection promoted a limited effect on placental TH metabolism, but increased the expression of placental inflammatory markers at term. We speculate that these changes may result in reduced TH transport from mother to fetus, leading to IUGR among surviving fetuses, especially in pregnancies threatened by MiP. Presentation: Friday, June 16, 2023

The metabolic response of human trophoblasts derived from term placentas to metformin

Aims/hypothesisMetformin is increasingly used therapeutically during pregnancy worldwide, particularly in the treatment of gestational diabetes, which affects a substantial proportion of pregnant women globally. However, the impact on placental metabolism remains unclear. In view of the association between metformin use in pregnancy and decreased birthweight, it is essential to understand how metformin modulates the bioenergetic and anabolic functions of the placenta.MethodsA cohort of 55 placentas delivered by elective Caesarean section at term was collected from consenting participants. Trophoblasts were isolated from the placental samples and treated in vitro with clinically relevant doses of metformin (0.01 mmol/l or 0.1 mmol/l) or vehicle. Respiratory function was assayed using high-resolution respirometry to measure oxygen concentration and calculated {dot{V}mathrm{O}}_{2}. Glycolytic rate and glycolytic stress assays were performed using Agilent Seahorse XF assays. Fatty acid uptake and oxidation measurements were conducted using radioisotope-labelled assays. Lipidomic analysis was conducted using LC-MS. Gene expression and protein analysis were performed using RT-PCR and western blotting, respectively.ResultsComplex I-supported oxidative phosphorylation was lower in metformin-treated trophoblasts (0.01 mmol/l metformin, 61.7% of control, p<0.05; 0.1 mmol/l metformin, 43.1% of control, p<0.001). The proton efflux rate arising from glycolysis under physiological conditions was increased following metformin treatment, up to 23±5% above control conditions following treatment with 0.1 mmol/l metformin (p<0.01). There was a significant increase in triglyceride concentrations in trophoblasts treated with 0.1 mmol/l metformin (p<0.05), particularly those of esters of long-chain polyunsaturated fatty acids. Fatty acid oxidation was reduced by ~50% in trophoblasts treated with 0.1 mmol/l metformin compared with controls (p<0.001), with no difference in uptake between treatment groups.Conclusions/interpretationIn primary trophoblasts derived from term placentas metformin treatment caused a reduction in oxidative phosphorylation through partial inactivation of complex I and potentially by other mechanisms. Metformin-treated trophoblasts accumulate lipids, particularly long- and very-long-chain polyunsaturated fatty acids. Our findings raise clinically important questions about the balance of risk of metformin use during pregnancy, particularly in situations where the benefits are not clear-cut and alternative therapies are available.Graphical

The Placental Metabolic Derangements and Fetal Complications in Gestational Diabetes Mellitus: A Literature Review

Gestational diabetes mellitus (GDM) is associated with adverse maternal and fetal complications including longer-term risk for developingT2DM, obesity and cardiovascular complications (CVD) later in their life. The placental derangements play a major role in the pathobiology of GDM. This review is aimed at to discuss the various aspects altered placental pathways in GDM, and where there are gaps in the literature that warrant further exploration. Published scientific manuscripts between 2000 and 2022 that discussed the role of insulin resistance, dyslipidaemia, oxidative stress and low-grade inflammation in the pathogenesis of GDM were reviewed. The main keywords used were insulin resistance, oxidative stress, lipid metabolism, dyslipidaemia, and low-grade inflammation. GDM is associated with maternal insulin resistance, dyslipidaemia, oxidative stress, and inflammation. These maternal derangements in GDM could affect placental and foetal lipid metabolism. The altered placental pathways could enhance the transfer of nutrients like glucose and FFA to the growing foetus causing overgrowth and adiposity. GDM foetuses experienced oxidative stress and inflammation and they could be involved in foetal programming for future metabolic diseases such as T2DM, obesity, CVD, etc. Understanding the various molecular mechanisms of placental derangements involved in the pathogenesis of GDM could expand our vision and open up avenues for therapeutic and preventive strategies for the better management of GDM women.

Triphenyl phosphate disrupts placental tryptophan metabolism by activating MAOA/ROS/NFκB

Triphenyl phosphate (TPhP) is an organophosphate flame retardant widely distributed in the environment. The neurodevelopmental toxicity of TPhP has been observed in animals and humans. Previously, we found that prenatal TPhP exposure disturbed placental tryptophan metabolism, impaired neurodevelopment in male offspring, and induced abnormal neurobehavior; however, the underlying mechanisms are unknown. In this study, using the trophoblast cell line JEG-3, we found that TPhP altered gene and protein expression in the tryptophan metabolism pathway, inhibited the tryptophan-serotonin pathway, and activated the tryptophan-kynurenine pathway. Meanwhile, TPhP induced oxidative stress by activating monoamine oxidase A (MAOA), promoting inflammatory factors including nuclear factor kappa-B (NFκB), interleukin-6, and tumor necrosis factor α. The NFκB inhibitor sulfasalazine could alleviate the effects of TPhP on tryptophan metabolism disturbance. The MAOA inhibitor clorgyline or the antioxidant N-acetylcysteine can mitigate oxidative stress and eliminate TPhP-induced inflammatory factors and tryptophan metabolism disturbances. The data above suggest that TPhP disturbed tryptophan metabolism by activating NFκB through MAOA-mediated oxidative stress. Finally, using the mouse intrauterine exposure model, the results confirmed that TPhP induced oxidative stress, activated inflammatory factors, disturbed tryptophan metabolism, and increased the levels of the tryptophan metabolites serotonin, kynurenine, 3-hydroxykynurenine, and 3-hydroxyanthranilic acid in the placenta during the second trimester of pregnancy. Overall, TPhP can disturb placental tryptophan metabolism by activating the inflammatory factor NFκB, which was induced by MAOA-induced oxidative stress. The results of this study confirm that indirect exposure to xenobiotic compounds at an early life stage can impair offspring development and provide a novel perspective on the neurodevelopmental toxicity of TPhP.

The role of creatine in placental energy metabolism at birth: Initial insights from the Creatine and Pregnancy Outcomes (CPO) cohort study of low-risk pregnancy

The role of creatine in placental energy metabolism at birth: Initial insights from the Creatine and Pregnancy Outcomes (CPO) cohort study of low-risk pregnancy

The impact of systemic inflammatory response on placental tryptophan metabolism in Wistar rats

The impact of systemic inflammatory response on placental tryptophan metabolism in Wistar rats

Maternal obesity and GDM affect regulation of placental protein metabolism in a fetal sex-dependent manner.

Maternal obesity and GDM affect regulation of placental protein metabolism in a fetal sex-dependent manner.

The in vitro effect of myo-inositol and scyllo-inositol on placental lipid metabolism

The in vitro effect of myo-inositol and scyllo-inositol on placental lipid metabolism

Chronic inhalation of titanium dioxide nanoparticles disrupts placental glucose transport and metabolism in a sex-dependent manner

Chronic inhalation of titanium dioxide nanoparticles disrupts placental glucose transport and metabolism in a sex-dependent manner

Placental tryptophan metabolism in health and disease; from bedside to bench and back

Placental tryptophan metabolism in health and disease; from bedside to bench and back

Placental transfer and metabolism of betamethasone in healthy and preeclamptic human placentas

Placental transfer and metabolism of betamethasone in healthy and preeclamptic human placentas

The impact of maternal exposure to micro-/nanoplastics on placental development, function and metabolism

The impact of maternal exposure to micro-/nanoplastics on placental development, function and metabolism

Effects of omega-3 fatty acid supplementation on placental lipid metabolism in vitro

Effects of omega-3 fatty acid supplementation on placental lipid metabolism in vitro

Characterization of a human placental clearance system to regulate serotonin levels in the fetoplacental unit

BackgroundSerotonin (5-HT) is a biogenic monoamine with diverse functions in multiple human organs and tissues. During pregnancy, tightly regulated levels of 5-HT in the fetoplacental unit are critical for proper placental functions, fetal development, and programming. Despite being a non-neuronal organ, the placenta expresses a suite of homeostatic proteins, membrane transporters and metabolizing enzymes, to regulate monoamine levels. We hypothesized that placental 5-HT clearance is important for maintaining 5-HT levels in the fetoplacental unit. We therefore investigated placental 5-HT uptake from the umbilical circulation at physiological and supraphysiological levels as well as placental metabolism of 5-HT to 5-hydroxyindoleacetic acid (5-HIAA) and 5-HIAA efflux from trophoblast cells.MethodsWe employed a systematic approach using advanced organ-, tissue-, and cellular-level models of the human placenta to investigate the transport and metabolism of 5-HT in the fetoplacental unit. Human placentas from uncomplicated term pregnancies were used for perfusion studies, culturing explants, and isolating primary trophoblast cells.ResultsUsing the dually perfused placenta, we observed a high and concentration-dependent placental extraction of 5-HT from the fetal circulation. Subsequently, within the placenta, 5-HT was metabolized to 5-hydroxyindoleacetic acid (5-HIAA), which was then unidirectionally excreted to the maternal circulation. In the explant cultures and primary trophoblast cells, we show concentration- and inhibitor-dependent 5-HT uptake and metabolism and subsequent 5-HIAA release into the media. Droplet digital PCR revealed that the dominant gene in all models was MAO-A, supporting the crucial role of 5-HT metabolism in placental 5-HT clearance.ConclusionsTaken together, we present transcriptional and functional evidence that the human placenta has an efficient 5-HT clearance system involving (1) removal of 5-HT from the fetal circulation by OCT3, (2) metabolism to 5-HIAA by MAO-A, and (3) selective 5-HIAA excretion to the maternal circulation via the MRP2 transporter. This synchronized mechanism is critical for regulating 5-HT in the fetoplacental unit; however, it can be compromised by external insults such as antidepressant drugs.