Placental Nutrient Transport Research Articles

Изменения в системе гемостаза у беременных с задержкой роста плода

Введение: Задержка роста плода (ЗРП) занимает второе место в структуре причин перинатальной смертности, а ее наличие имеет длительное неблагоприятное влияние на здоровье ребенка. Оценка степени активации системы гемостаза при ЗРП в сопоставлении с клиническими исходами имеет важное значение в понимании патогенеза, улучшении прогнозирования и профилактики этого патологического состояния. Цель исследования: оценить состояние гемостаза у беременных с ЗРП в сравнении с женщинами с физиологическим течением беременности. Материалы и методы: Тип исследования: поперечный срез на базе когортного. В исследование включено 52 беременных. Основная группа — 32 пациентки с ЗРП, выявленной при ультразвуковой фетометрии; контрольная группа — 20 практически здоровых женщин без отягощенного акушерско-гинекологического анамнеза, с физиологически протекавшей беременностью, завершившейся неосложненными родами. Оценку состояния системы гемостаза проводили на сроке 24-32 нед гестации. Результаты: Среди факторов тромботического риска у беременных с ЗРП чаще выявлялось табакокурение во время беременности. Наличие ЗРП было значимо связано с маловодием, генитальной и внутриматочной инфекцией, преэклампсией, нарушениями маточно-плацентарно-плодового кровотока. У женщин с ЗРП обнаружен более высокий уровень фибриногена, а также повышение скорости роста сгустка, больший размер сгустка, более частое формирование спонтанных сгустков в сравнении с контрольной группой. Заключение: У беременных с ЗРП имеется протромботическая готовность плазмы, что может служить основанием для дальнейшей разработки антитромботической коррекции с целью улучшения перинатальных исходов. Background: Fetal growth retardation (FGR) is the second leading cause of perinatal mortality, has a long-term adverse effect on child health. Assessment of hemostasis activation in FGR in comparison with clinical outcomes is important for understanding pathogenesis, improving the prognosis and prevention of this pathological state. Objectives: to assess hemostasis state in pregnant women with FGR compared to women with physiological pregnancy. Patients/Methods: Type of study: crosssectional based on cohort. The study included 52 pregnant women. The main group consisted of 32 patients with FGR diagnosed by ultrasound fetometry; the control group consisted of 20 practically healthy women without burdened obstetric-gynecological history, with physiological pregnancy that ended in uncomplicated childbirth. Hemostasis assessment was carried out at 24-32 weeks of gestation. Results: Smoking during pregnancy as a factor of thrombotic risk was more common in pregnant women with FGR. FGR was significantly associated with oligohydramnios, genital and intrauterine infection, preeclampsia, and placental insufficiency. Women with FGR showed a higher level of fibrinogen, as well as an increased rate of clot growth, clot larger size, and more frequent formation of spontaneous clots in comparison with the control group. Conclusions: Pregnant women with FGR are characterized by prothrombotic state that may be the basis for further development of antithrombotic correction for improving perinatal outcomes.

Maternal Obesity Influences Placental Nutrient Transport, Inflammatory Status, and Morphology in Human Term Placenta.

Maternal obesity has a significant impact on placental development. However, this impact on the placenta's structure and function (ie, nutrient transport and hormone and cytokine production) is a controversial subject. We hypothesized that maternal obesity is associated with morphologic, secretory, and nutrient-related changes and elevated levels of inflammation in the placenta. We collected samples of placental tissue from 2 well-defined groups of pregnant women from 2017 to 2019. We compared the 2 groups regarding placental cytokine and hormone secretion, immune cell content, morphology, and placental nutrient transporter expressions. Placenta were collected after caesarean section performed by experienced clinicians at Centre Hospitalier Intercommunal (CHI) of Poissy-Saint-Germain-en-Laye. The main inclusion criteria were an age between 27 and 37 years old, no complications of pregnancy, and a first-trimester body mass index of 18-25 kg/m2 for the nonobese (control) group and 30-40 kg/m2 for the obese group. In contrast to our starting hypothesis, we observed that maternal obesity was associated with (1) lower placental IL-6 expression and macrophage/leukocyte infiltration, (2) lower placental expression of GLUT1 and SNAT1-2, (3) a lower placental vessel density, and (4) lower levels of placental leptin and human chorionic gonadotropin production. These results suggest that the placenta is a plastic organ and could optimize fetal growth. A better understanding of placental adaptation is required because these changes may partly determine the fetal outcome in cases of maternal obesity.

Maternal PM2.5 exposure and abnormal placental nutrient transport

Epidemiological studies of human and animal experiments indicated that gestational exposure to atmospheric pollutants could be followed by the abnormal placental development. However, the effects of this exposure on the placental transportation for nutrients have not been systematically investigated. In this study, fine particulate matters (PM2.5) samples were collected in Taiyuan and pregnant rodent models were administered with 3 mg/kg b.w. PM2.5 by oropharyngeal aspiration every other day starting on embryonic day 0.5 (E0.5). Then the pregnant mice were sacrificed and their placentas were collected at different time points. The results showed that maternal PM2.5 exposure (MPE) disrupted the expression of proliferating cell nuclear antigen (PCNA) at all time points and inhibited the cell proliferation in placenta. Following that, the capacity for placental nutrient transport was impaired. The changes at E18.5 were observed most significantly, showing the altered mRNA expression of amino acid, long-chain polyunsaturated fatty acid (LCPUFA), glucose and folate transporters. In addition, the glycogen content was elevated at E18.5, and the triglyceride content was increased at E13.5 and E15.5 and decreased at E18.5 in the placenta after MPE. In a word, the adverse effect induced by MPE revealed that MPE led tothe disruption on the nutrient supply to the developing fetus via modulating the abundance of placental nutrient transporters (PNT).

Abnormalities of placental development and function are associated with the different fetal growth patterns of hypoplastic left heart syndrome and transposition of the great arteries

BackgroundBirthweight is a critical predictor of congenital heart disease (CHD) surgical outcomes. Hypoplastic left heart syndrome (HLHS) is cyanotic CHD with known fetal growth restriction and placental abnormalities. Transposition of the great arteries (TGA) is cyanotic CHD with normal fetal growth. Comparison of the placenta in these diagnoses may provide insights on the fetal growth abnormality of CHD. MethodsClinical data and placental histology from placentas associated with Transposition of the Great Arteries (TGA) were analyzed for gross pathology, morphology, maturity and vascularity and compared to both control and previously analyzed HLHS placentas [1]. RNA was isolated from HLHS, TGA and control placentas and sequenced by Illumina HiSeq.Transcriptome analysis was performed using AltAnalyze. Immunohistochemistry was utilized to assess placental nutrient transporter expression in all three groups. ResultsPlacental weight was reduced in TGA cases, and demonstrated reduced villous vasculature, immature terminal villi in the parenchyma compared to controls and reflected our previous data from HLHS placentas. However, birth weight was not reduced in TGA cases compared to controls in contrast to the HLHS cohort and birthweight:placental weight ratio was significantly increased in TGA cases but not HLHS compared to control. Transcriptomic and histologic analysis demonstrates reduced cell activity and nutrient transport capability in HLHS but not TGA placentas which appear to increase/maintain these mechanisms. ConclusionsDespite common vascular disturbances in placentas from HLHAs and TGA, these do not account for the disparities in birthweights frequently seen between these CHD subtypes, in contrast our transcriptomic and histologic analyses reveal differentially regulated mechanisms between the subtypes that may explain these disparities.

Abstract P218: Tumor Necrosis Factor Alpha Improves Placental Perfusion And Attenuates Intrauterine Growth Restriction In A Rodent Model Of Preeclampsia

Preeclampsia ( PE ) is not only detrimental to the mother and her fetus during pregnancy, but it is also associated with increased cardiovascular ( CV ) risk in the mother and her intrauterine growth restricted ( IUGR ) offspring in later life. Currently there are no known treatment options for PE beyond early delivery. Thus, there is a critical need to identify therapeutic treatments for PE. The inflammatory cytokine TNF-α is increased in women with PE. In the clinically relevant Reduced Uterine Perfusion Pressure ( RUPP ) model of PE in the rat, TNF-α is also increased and importantly, etanercept abolishes maternal hypertension. Etanercept is a soluble receptor that binds TNF-alpha to inhibit the inflammatory response. Although not yet prescribed for PE, etanercept is non-contraindicated during pregnancy. Therefore, this study tested the hypothesis that maternal administration of etanercept will mitigate IUGR in the RUPP model of PE and that improvement in fetal growth occurs in association with improved uteroplacental perfusion, placental morphology, and placental nutrient transporter protein expression. Sham or RUPP was performed at gestational day 14 ( G14 ). Dams were administered vehicle or the TNF-α inhibitor (etanercept, 0.4 mg/kg, s.c.) at G18. At G20 uterine artery resistance index ( UARI ) was significantly increased in vehicle RUPP (0.69±0.02 mm/s) vs. vehicle Sham (0.60±0.02mm/s)( p <0.05), indicative of reduced uteroplacental perfusion, but UARI was no longer increased in treated RUPP (0.65±0.03 mm/s)( p <0.05). At G20, fetal weight was significantly reduced in vehicle RUPP (3.52g±0.10) vs. vehicle Sham (3.82 g±0.09)( p <0.05). Yet, fetal weight was significantly increased in treated RUPP (3.82g±0.12) vs. vehicle RUPP ( p <0.05). Fetal brain weight did not differ in Sham or RUPP, regardless of maternal treatment. However, fetal liver weight was significantly increased in treated RUPP (0.29g ±0.02) vs. vehicle RUPP (0.24g±0.01)( p <0.05) suggesting attenuation of asymmetric growth restriction. These findings indicate that maternal administration of a TNF-α inhibitor during PE improves fetal growth in association with improved uteroplacental blood flow. Future studies are warranted to investigate the long-term benefit in IUGR offspring.

Maternal supplementation with uridine influences fatty acid and amino acid constituents of offspring in a sow-piglet model.

To investigate the cumulative effects of maternal supplementation with nucleotides in the form of uridine (UR) on fatty acid and amino acid constituents of neonatal piglets, fifty-two sows in late gestation were assigned randomly into the control (CON) group (fed a basal diet) or UR group (fed a basal diet with 150 g/t UR). Samples of neonates were collected during farrowing. Results showed that supplementing with UR in sows' diet significantly decreased the birth mortality of pigs (P = 0·05), and increased serum total cholesterol, HDL and LDL of neonatal piglets (P < 0·05). Moreover, the amino acid profile of serum and liver of neonatal piglets was affected by the addition of UR in sows' diets (P < 0·05). Furthermore, an up-regulation of mRNA expression of energy metabolism-related genes, including fatty acid elongase 5, fatty acid desaturase 1, hormone-sensitive lipase and cholesterol-7a-hydroxylase, was observed in the liver of neonates from the UR group. Additionally, a decrease in placental gene expression of excitatory amino acid transporters 2, excitatory amino acid transporter 3 and neutral AA transporter 1 in the UR group was concurrently observed (P < 0·05), and higher protein expression of phosphorylated protein kinase B, raptor, PPARα and PPARγ in placenta from the UR group was also observed (P < 0·05). Together, these results showed that maternal UR supplementation could regulate placental nutrient transport, largely in response to an alteration of mTORC1-PPAR signalling, thus regulating the nutrition metabolism of neonatal piglets and improving reproductive performance.

Paternal High Fat Diet and Exercise Regulate Sperm miRNA to Alter Placental Inflammation and Nutrient Transporter Expression in a Sex-Dependent Manner

Abstract Objectives We have shown that male offspring (F1) of fathers (F0) fed a high fat (HF) diet and exercised had greater skeletal muscle insulin signaling and reduced T2DM risk compared to fathers fed HF diet and remain sedentary. The current study extends this work by hypothesizing that F0 HF diet and exercise regulate F1 T2DM risk by early alterations in epigenetics of placental tissue growth via changes in sperm miRNA expression. Methods To test these hypotheses, three-week old male C57BL/6 mice were fed a normal-fat (NF) diet (16% fat) or a HF diet (45% fat) and assigned to either voluntary wheel running exercise or cage activity for 3 months prior to mating with NF diet fed dams. F0 sperm and placental tissue samples were collected to determine changes in placental and fetal weights, placental gene expression, and F0 sperm miRNA expression. Results F0 sperm miRNA 193b expression was decreased while miRNA 204 was increased by paternal exercise. Protein expression of di-methylated histone 3 lysine 9 was decreased with F0 HF diet. Placental and fetal tissue weights were decreased by F0 HF diet in F1 males while no changes in the F1 females. Placental proinflammatory cytokine mRNA expression, including IL-1 beta and TNF-alpha, was reduced by paternal exercise while nutrient transporter mRNA expression was decreased by paternal HF diet only in the placentae of F1 females. Treatment of primary placental cell with miRNA 193 inhibited TNF-alpha mRNA expression. In addition, treatment of the same cells with TNF-alpha increased SLC6a19. Moreover, paternal exercise increased body weight at weaning in a female offspring. Conclusions These results demonstrate that placental tissue weight, placental nutrient transporter gene expression and fetal weights are altered by paternal exercise while placental inflammatory gene expression are influenced by paternal exercise in offspring in a sex-specific manner. Funding Sources This work was supported by USDA ARS Project #3062–51,000-054–00D.

Is there a definite relationship between placental mTOR signaling and fetal growth?

Fetal growth restriction and overgrowth are common obstetrical complications that result in adverse perinatal outcomes and long-term health risks later in life, including neurodevelopmental dysfunction and adult metabolic syndrome. The placenta plays a critical role in the nutrition transfer from mother to fetus and even exerts adaptive mechanism when the fetus is under poor developmental conditions. The mammalian/mechanistic target of rapamycin (mTOR) signaling serves as a critical hub of cell growth, survival, and metabolism in response to nutrients, growth factors, energy, and stress signals. Placental mTOR signaling regulates placental function, including oxygen and nutrient transport. Therefore, placental mTOR signaling is hypothesized to have a positive relationship with fetal growth. In this review, we summarize that most studies support the current evidence that there is connection between placental mTOR signaling and abnormal fetal growth; however, but more studies should be performed following a vigorous and unanimous method for assessment to determine placental mTOR activity.

Effects of Maternal Obesity On Placental Phenotype.

The incidence of obesity is rising rapidly worldwide with the consequence that more women are entering pregnancy overweight or obese. This leads to an increased incidence of clinical complications during pregnancy and of poor obstetric outcomes. The offspring of obese pregnancies are often macrosomic at birth although there is also a subset of the progeny that are growth-restricted at term. Maternal obesity during pregnancy is also associated with cardiovascular, metabolic and endocrine dysfunction in the offspring later in life. As the interface between the mother and fetus, the placenta has a central role in programming intrauterine development and is known to adapt its phenotype in response to environmental conditions such as maternal undernutrition and hypoxia. However, less is known about placental function in the abnormal metabolic and endocrine environment associated with maternal obesity during pregnancy. This review discusses the placental consequences of maternal obesity induced either naturally or experimentally by increasing maternal nutritional intake and/or changing the dietary composition. It takes a comparative, multi-species approach and focusses on placental size, morphology, nutrient transport, metabolism and endocrine function during the later stages of obese pregnancy. It also examines the interventions that have been made during pregnancy in an attempt to alleviate the more adverse impacts of maternal obesity on placental phenotype. The review highlights the potential role of adaptations in placental phenotype as a contributory factor to the pregnancy complications and changes in fetal growth and development that are associated with maternal obesity.

OR20-02 Maternal Adiponectin Prevents Against Metabolic Dysfunction in Prenatally Androgenized PCOS-Like Mice

More than 10% of women worldwide are diagnosed with polycystic ovary syndrome (PCOS), causing reproductive and metabolic disease. Hyperandrogenism is the main characteristic and elevated levels of androgens during pregnancy affect placenta function and fetal programming, which leads to reproductive and metabolic dysfunction in the offspring. Adiponectin secreted from adipose tissue improves whole-body metabolism, but its role during pregnancy is under explored. Adiponectin affects placental nutrient transport during pregnancy allowing for speculation that adiponectin can exert endocrine effects on the developing fetus. This study aims to investigate if, in prenatally androgenized (PNA) mice, adiponectin can prevent metabolic and reproductive dysfunction in female offspring. Adiponectin transgenic (APNtg) and wildtype (wt) female mice were mated with wt males, and received dihydrotestosterone or vehicle injections between gestational days 16.5-18.5 to induce a PCOS-like phenotype. The anogenital distance, a marker of in utero androgen exposure, was measured at 22 days of age, estrus cyclicity was recorded at 6 weeks of age, and metabolic measures were performed at 4 months of age.APNtg dams gave birth to significantly smaller offspring, independent of genotype, than wt dams. PNA increased f-insulin in all groups but insulin sensitivity was higher in wt mice from APNtg dams compared to wt mice from wt dams. Insulin resistance correlated with subcutaneous and visceral fat mass. PNA increased visceral fat % and adipocyte size in wt offspring from wt dams while wt and APNtg offspring from APNtg dams were protected against this effect. Visceral adipose tissue gene expression was unaltered in PNA wt offspring, regardless of the dam’s genotype, while APNtg offspring, regardless of PNA, had increased expression of adipogenic genes. Anogenital distance was increased in all PNA wt offspring independent of the dam’s genotype. There was, however, no difference between APNtg-vehicle and APNtg-PNA mice, suggesting that adiponectin overexpression protects against this effect. PNA leads to disrupted estrous cycle and fewer ovulations, but this effect was less pronounced in PNA wt mice from APNtg dams. Our data suggests that elevated maternal adiponectin protects the offspring against PNA induced metabolic dysfunction, and to a lesser extent reproductive dysfunction.

L-carnitine increases cell proliferation and amino acid transporter expression via the activation of insulin-like growth factor I signaling pathway in rat trophoblast cells.

Early embryo implantation and development is primarily determined by the homeostasis between cellular apoptosis and proliferation as well as placental nutrient transporters. Recent studies showed that L‐carnitine enhances female reproductive performance. However, the potential function of L‐carnitine on placenta is largely unknown. In our study, primary rat trophoblast cells were separated and cultured for 12 hr in medium containing various concentrations of L‐carnitine (0, 1, 10, and 50 mM). Placenta trophoblast cells treated with 50 mM L‐carnitine increased the proportion of cells in S phase of the cell cycle (p < .05). In addition, live cell percentage was increased when treated with either 10 mM or 50 mM L‐carnitine, which was accompanied with decreased necrotic cells, late apoptotic cells, and early apoptotic cells (p < .05). Compared with the control treatment, the mRNA expression of insulin‐like growth factor I (IGF‐1) and insulin‐like growth factor I receptor (IGF‐1R) was higher in rat placenta trophoblasts treated with either 10 mM or 50 mM L‐carnitine (p < .05). Similarly, sodium‐dependent neutral amino acid transporter (SNAT)‐1 and SNAT2 were up‐regulated in both mRNA and protein levels when trophoblast cells were treated with 50 mM L‐carnitine (p < .05). Inhibiting downstream targets (Akt or ERK signaling pathways) of IGF‐1 signaling pathway partially blocked the effect the L‐carnitine‐induced increase in protein abundances of SNAT1 and SNAT2. Collectively, our data showed protective role of L‐carnitine on placenta trophoblast cells through the involvement of IGF‐1 signaling pathway.

Elevated maternal linoleic acid alters placental fatty acids, nutrient transporters and inflammatory proteins

Linoleic acid (LA) is the major omega‐6 fatty acid which is obtained from our diet. During pregnancy, LA is required for adequate fetal growth and development. For the growing fetus LA can only be obtained from the maternal diet, and is transferred from the maternal to fetal circulations by the placenta. At this time, in Western societies, we are overconsuming LA during pregnancy. Omega‐6 is metabolised by FADS1 and FADS2, which also metabiolise omega‐3. The ratio of omega‐6 to omega‐3 is important for human health, as they are proinflammatory and anti‐inflammatory, respectively. Therefore, the aim of this study is to determine if elevated maternal LA during pregnancy is alters placental fatty acids, nutrient transporter gene expression and inflammatory proteins.Female Wistar Kyoto rats were fed a diet low in LA (LLA‐1.44% of energy) or diet high in LA (HLA‐6.21% of energy) for 10 weeks before and during gestation. Following mating with a male consuming normal chow, offspring and maternal rats were sacrificed at embryonic day (E)20, and placenta were collected for analysis of placental fatty acids, nutrient transporters and inflammatory markers.In isolated placenta from pregnancies where mothers consumed an elevated LA diet, the concentration of LA was increased and the concentration of the omega‐3 fatty acid a‐linoleinic acid was decreased. Of interest, the downstream metabolite of LA, arachidonic acid was not altered in placenta from mothers consuming an elevated LA diet. mRNA expression of slc27a1 (fatty acid trasnport protein 1) was significantly downregulated in the male placenta from the dams fed with HLA, but not females. The mRNA expression of slc2a1 (glucose trasnporter 1) was significantly decreased in both male and female placenta from mothers fed the HLA diet. Further, the protein concentration of interleukin‐7 (IL‐7) was significantly decreased in both male and female placenta (labyrinth) from the dams fed with HLA, however there were no changes in protein expression of IL‐6 and TNF‐α in the labyrinth.In conclusion, a maternal diet high in LA alters fatty acid concentrations, nutrient transporters and inflammatory cytokines in the placenta. The consequences of this on offspring development, and therefore long term health require further investigation.Support or Funding InformationAllen Foundation (USA)

Soluble Guanylate Cyclase in a Rodent Model of Preeclampsia: Is Benefit in the Mother Associated with Benefit in the Offspring?

The initiating event in preeclampsia (PE) involves improper placental remodeling, placental ischemia, maternal hypertension and asymmetric intrauterine growth restriction (IUGR). IUGR offspring have increased risk for chronic disease such as hypertension and cardiovascular disease. Currently, the only treatment option for PE is delivery of the baby and placenta. Therefore, identifying maternal therapies for treatment for PE that do not inflict harm on the developing fetus are crucial. Nitric oxide (NO) is reduced in PE resulting in reduced blood flow and increased maternal blood pressure. Soluble guanylate cyclase (sGC) inducers, a component of the NO pathway, reduce maternal blood pressure and improve reduced fetal weight in a rodent model of PE induced by reduced uterine perfusion pressure (RUPP). However, the long‐term benefit or harm in the offspring is unknown. Thus, this study tested the hypothesis that maternal treatment with a sGC inducer will improve uterine blood flow and placental nutrient transport resulting in improvement in asymmetric growth restriction in the RUPP model of PE. Sham or RUPP was performed at day 14 of gestation followed by administration of vehicle or a sGC inducer (riociguat, 10mg/kg/day, s.c.) until gestation day 20 (G20) or birth. At G20 uterine artery resistance index (UARI) was significantly increased, indicative of poor placental perfusion, in vehicle‐treated RUPP (0.64±0.01 mm/s) vs. vehicle‐treated Sham (0.57±0.01 mm/s) (p&lt;0.05), but was also increased in sGC‐treated Sham (0.64±0.01 mm/s) vs. vehicle‐treated Sham (p&lt;0.05). Placental nutrient transporter heart fatty acid binding protein (hFABP) protein expression was also significantly increased in vehicle‐treated RUPP (821.5±55.6 A.U.) vs. vehicle‐treated Sham (588.8±30.4 A.U.) (p&lt;0.05). Yet, placental hFABP protein expression was also significantly increased in sGC‐treated Sham (814.7±77.4 A.U.)(p&lt;0.05); up‐regulation that may be a compensatory mechanism to maintain normal brain development. Although an increase in gestational length in women with risk of PE‐associated preterm delivery is beneficial, gestational length at birth was significantly lengthened in full‐term sGC‐treated RUPP, an increase of 24 hours vs. vehicle‐treated Sham. Asymmetric growth at birth was not abolished and treatment in the RUPP was associated with a significant decrease in survival at birth (26.3%±6.5 survival rate versus 62.3%±10.0 survival rate, sGC‐treated RUPP vs. vehicle‐treated Sham; p&lt;0.05). Pup weight at birth was not asymmetric but was reduced in sGC‐treated Sham (5.3±0.2 grams) vs. vehicle‐treated Sham (5.9±0.2 grams) (p&lt;0.05). Thus, these findings indicate that maternal interventions using sGC inducers during PE may not provide benefit to the developing fetus despite improvement in maternal blood pressure implicating caution in the translation of this agent to the clinical setting. Future studies will investigate the long‐term effect of this maternal therapeutic on cardiovascular risk in the offspring born to Sham and RUPP dams.Support or Funding InformationHL143459, P20GM121334, P20GM104357, HL51971, T32HL105324

Maternal Iron Deficiency Elicits Changes in Placental Development and Alters Fetal Growth Trajectories

Iron is an essential mineral that participates in oxygen transport, DNA synthesis and repair, and as a cofactor for various cellular processes. Iron deficiency (ID) is the most common nutritional deficiency worldwide and pregnant women are one of the populations most at risk. ID during pregnancy poses major health concerns for the developing baby, including fetal growth restriction and long‐term health complications. Maternal ID may indirectly impair fetal growth through changes in the structure and function of the placenta, however, the effect of ID on the placenta is not well understood.ObjectiveThis project aims to establish a model of ID in pregnant rats and investigate the resulting changes in placental development and fetal growth.MethodsPregnant Sprague‐Dawley rats were fed either a low iron (10 mg iron/kg) or iron‐replete (37 iron/kg) diet starting two weeks before pregnancy to induce a state of ID anemia alongside respective controls. Detection of sperm in a vaginal lavage was designated gestational day (GD) 0.5. Conceptuses were dissected at either GD 13.5 or GD 18.5. Dam and fetal hemoglobin (Hb) concentration and body weight were measured. Placentas were weighed, cryosectioned and stained with hematoxylin and eosin to assess the cross‐sectional areas of the labyrinth and junctional zones (anatomical units of the rodent placenta). Placental mRNA expression of iron transporters and other nutrient transporters was measured by Clariom S microarray.ResultsCompared to controls, ID reduced maternal hemoglobin (Hb) throughout pregnancy, including a 44% (P=0.0006) reduction on GD 18.5. Fetal Hb was also reduced in ID on GD 18.5 by 47% (P&lt;0.0001). ID caused a 14% (P=0.03) reduction in total fetal body weight and reduced fetal liver weight by 18% (P=0.003) compared to controls. There was no change in fetal brain, heart or kidney weight. Interestingly, relative placental size was increased in ID by 33% (P=0.0008), including a 27% (P=0.007) increase in junctional zone area and no change in labyrinth zone area.ConclusionMaternal ID was associated with the development of anemia in both moms and fetuses. ID also decreased fetal weight and increased placental growth, specifically in the junctional zone.Significance and ImplicationsDecreased iron availability and oxygen‐carrying capacity in pregnancy may stimulate placental structural changes as a compensatory response to maintain fetal nutrition and oxygenation. Although such adaptations may provide short‐term benefits to the baby, they may ultimately lead to placental insufficiency and failure to meet fetal demands, resulting in fetal growth restriction. Since the placenta forms the interface between a mother and her baby, these modifications may yield new diagnostic indices of fetal distress in ID pregnancies, such as placental size changes that can be detected by ultrasound or post‐partum analysis of placental nutrient transporters and markers of inflammation. Knowledge of such changes may, therefore, lead to earlier interventions and improved fetal outcomes.Support or Funding InformationCanadian Institutes of Health Research

Paternal high-fat diet and exercise regulate sperm miRNA and histone methylation to modify placental inflammation, nutrient transporter mRNA expression and fetal weight in a sex-dependent manner

We previously have shown that male offspring (F1) of fathers (F0) fed a high-fat (HF) diet and that exercised had greater skeletal muscle insulin signaling and reduced type 2 diabetes mellitus (T2DM) risk compared to fathers fed HF diet and that remained sedentary. The current study extends this work by hypothesizing that F0 HF diet and exercise regulate F1 T2DM risk by alterations in placental tissue growth via changes in sperm miRNA expression. To test these hypotheses, 3-week-old male C57BL/6 mice were fed a normal-fat diet (16% fat) or an HF diet (45% fat) and assigned to either voluntary wheel running exercise or cage activity for 3 months. Results showed that F0 sperm miRNA 193b expression was decreased while miRNA 204 was increased by paternal exercise. Protein expression of dimethylated histone 3 lysine 9 was decreased with F0 HF diet. Placental and fetal tissue weights were decreased by F0 HF diet in F1 males. Placental interleukin-1β and tumor necrosis factor (TNF)-α mRNA expression was reduced by paternal exercise, while nutrient transporter mRNA expression was decreased by paternal HF diet only in the placentae of F1 females. Treatment of primary placental cell with miRNA 193b inhibited TNF-α mRNA expression, and treatment of TNF-α decreased SLC38a2 mRNA expression. Moreover, paternal exercise increased body weight at weaning in a female offspring. These results demonstrate that placental tissue weight, placental nutrient transporter gene expression and fetal weights are altered by paternal exercise, while placental inflammatory gene expression is influenced by paternal exercise in offspring in a sex-specific manner.

Prenatal dexamethasone exposure exerts sex-specific effect on placental oxygen and nutrient transport ascribed to the differential expression of IGF2.

BackgroundClinical studies have showed that dexamethasone exposure during pregnancy could cause fetal growth retardation, but the mechanism by which prenatal dexamethasone exposure influences placental nutrient transport is still unclear. This study investigated the impacts of prenatal dexamethasone on the placental oxygen and nutrient transport.MethodsPregnant Wistar rats were subcutaneously administered with dexamethasone from day 9 to day 20 of gestation at 0.2 or 0.8 mg/kg·d. Pregnant rats were sacrificed on gestational day 20. The placental tissue was collected for analysis.ResultsPrenatal dexamethasone exposure (PDE) declined the fetal weight and increased the intrauterine growth retardation (IUGR) rate in a dose-dependent manner. The total placental volume and the length, density and surface area of fetal capillaries in the labyrinth zone reduced in a dose-dependent manner. In addition, the thickness of syncytial membrane dose-dependently increased, resulting in a dose-dependent decrease in oxygen diffusion capacity. Furthermore, after PDE, the nutrient transport area and oxygen diffusion capacity of male placenta were lower than that of female placenta. The mRNA and protein expression of placental nutrient transporters including glucose transporter 1 (GLUT1), glucose transporter 3 (GLUT3), L-type amino acid transporter 1 (LAT1), lipoprotein lipase (LPL) and scavenger receptor class B type 1 (SRB1) increased in female placenta. However, in male placenta, the expression of LAT1, LPL and SRB1 was significantly decreased and GLUT1 and GLUT3 have a decrease trend. We further investigated the expression of insulin-like growth factor 1 (IGF1) and insulin-like growth factor 2 (IGF2) related to placental and fetal growth and development. Our study showed that the expression of IGF1 was significantly decreased both in male and female placentas after PDE. But the expression of IGF2 was significantly increased in female placentas while significantly decreased in male placentas.ConclusionsOur study shows prenatal dexamethasone exposure exerts sex-specific influence on the placental oxygen and nutrient transport. This might be ascribed to the differential expression of IGF2 after PDE. These findings provide evidence on the dexamethasone-induced toxicity to the placenta and fetal development.

Associations between maternal body mass index and diet composition with placental DNA methylation at term

IntroductionMaternal obesity and poor quality diets are associated with greater risk of obesity in offspring. Maternal diet and obesity influence placental gene expression and nutrient transport, but the impact of diet and obesity on global epigenetic changes in the placenta are poorly understood. We hypothesized that placental DNA methylation patterns are associated with maternal body mass index (BMI) and/or maternal diet composition. MethodsUsing reduced representation bisulfite sequencing (RRBS), we assessed genome scale DNA methylation of ~300,000 CpGs in 150 term placentas from normal weight mothers (n = 72) and overweight/obese mothers (n = 78). Maternal BMI was assessed before week 10 of gestation and maternal diet composition was assessed using 3-day food records at each trimester. ResultsIn multivariable linear regression models, maternal BMI category (normal weight or overweight/obese), BMI (kg/m2), and maternal saturated fat consumption (g/d) were associated (p < 0.0001) with methylation of 185, 103, and 302 CpGs, respectively. Of the 56 CpGs associated with both maternal BMI category and maternal BMI (p < 0.0001), GO analysis showed biological processes related to SREBP signaling, phospholipid transport, granulocyte differentiation, and RNA pol II transcription to be affected. Maternal saturated fat intake was associated with methylation of 302 CpGs (p < 0.0001). These genes were related to chromatin remodeling, IGF receptor, PI3K, and nitric oxide synthase signaling. DiscussionThese data suggest that placental DNA methylation status is associated with both maternal obesity and maternal saturated fat intake, possibly contributing to maternal obesity-associated changes in placental function.

Changes in Placental Nutrient Transporter Protein Expression and Activity Across Gestation in Normal and Obese Women.

Fetal growth and development are dependent on placental nutrient transport. The syncytiotrophoblast (ST) and its two polarized plasma membranes, the maternal-facing microvillous membrane (MVM) and fetal-facing basal membrane (BM), represent the primary barrier in the human placenta, controlling transplacental transfer of small solutes. MVM and BM nutrient transporter expression and activity are increased in obese mothers delivering large babies. However, placental nutrient transporter expression and activity in early gestation in normal and obese women are largely unknown. Placentas from normal BMI and obese women at 6-24weeks of gestation, and term placentas from normal BMI women, were collected and ST plasma membranes isolated. The activity and protein expression of amino acid, glucose, and fatty acid transporters was assessed. No significant differences were observed in placental nutrient transporter protein expression between normal BMI and obese women in early pregnancy. In the MVM, system A amino acid activity (p = 0.02), SNAT2 (p < 0.0001), SNAT4 (p < 0.001), and GLUT1 (p = 0.01) protein expression were higher at term compared with early gestation. In contrast, MVM system L activity (p = 0.001), FATP4 (p = 0.03), and FATP6 (p = 0.009) protein expression were lower at term compared with early pregnancy. In the BM, there was no change in system L activity across gestation; however, BM FATP6 (p = 0.002) protein expression was lower at term compared with early pregnancy. These results suggest that placental transport of amino acids, glucose, and fatty acids are subjected to coordinated regulation across gestation to meet a fetal nutrient demand that changes with advancing pregnancy.

Child Head Circumference and Placental MFSD2a Expression Are Associated to the Level of MFSD2a in Maternal Blood During Pregnancy.

Gestational diabetes mellitus (GDM) is a world-wide health challenge, which prevalence is expected to increase in parallel to the epidemic of obesity. Children born from GDM mothers have lower levels of docosahexaenoic acid (DHA) in cord blood, which might influence their neurodevelopment. Recently, the membrane transporter Major Family Super Domain 2a (MFSD2a) was associated with the selective transportation of DHA as lysophospholipids. The expression of the DHA membrane transporter MFSD2a is lower in GDM placentas, which could affect materno-fetal DHA transport. Humans with homozygous inactivating mutations in the MFSD2a gene present severe microcephaly and intellectual impairments. Herein, we intended to identify early blood biomarkers that may be of use during pregnancy to monitor the offspring development and the adequate nutritional interventions, such as nutritional supplementation, that may be selected to improve it. We evaluated MFSD2a expression in maternal blood at the third trimester of pregnancy, and its potential relationship with the expression of placental MFSD2a at delivery and child outcomes. Three groups of pregnant women were recruited: 25 controls, 23 GDM with dietary treatment, and 20 GDM with insulin treatment. Maternal and neonatal anthropometric and biochemical parameters were evaluated. MFSD2a was analyzed in placenta, blood and serum. MFSD2a protein expression in maternal blood was significantly lower in GDM groups and correlated with placental MFSD2a and Z-score neonatal head circumference during the first 6 months of life. The cord/maternal serum ratio of DHA, a solid indicator of materno-fetal DHA transport, was reduced in GDM groups and correlated with MFSD2a in maternal blood at the third trimester and in placenta at delivery. This indicates that altered MFSD2a levels in maternal blood during pregnancy might influence placental nutrient transport and fetal neurodevelopment. Furthermore, MFSD2a levels in maternal blood on the third trimester were inversely correlated to DHA in maternal serum lyso-PL. Thus, the level of MFSD2a in maternal blood could be used as a potential biomarker for the early detection of disturbances of MFSD2a expression during pregnancy and the subsequent consequences for the neurodevelopment of the child, as well as it may help to choose the optimal treatment approach for the affected subjects.

Fetal Distribution of Feto-placental Blood Flow Related to Placental Nutrient Transport and Maternal Food Intake

Fetal Distribution of Feto-placental Blood Flow Related to Placental Nutrient Transport and Maternal Food Intake