Fetal programming occurs when the normal pattern of fetal development is disrupted by an abnormal stimulus or âinsultâ applied
at a critical point in in utero development. This then leads to an ...effect, for example diabetes or hypertension, which manifests itself in adult life. As
the placenta is the regulator of nutrient composition and supply from mother to fetus and the source of hormonal signals that
affect maternal and fetal metabolism, appropriate development of the placenta is crucial to normal fetal development. Placental
function evolves in a carefully orchestrated developmental cascade throughout gestation. Disruption of this cascade can lead
to abnormal development of the placental vasculature or of the trophoblast. Timing of a developmental âinsultâ will be critical
in consequent placental function and hence programming of the fetus. The âinsultsâ that alter placental development include
hypoxia and abnormal maternal nutrient status, to which the placenta may adapt by alterations in transporter expression and
activity to maintain fetal growth or by epigenetic regulation of placental gene expression. Hypoxia is physiological for organogenesis
and placental tissue normally exists in a relatively hypoxic environment, but intrauterine growth restriction (IUGR) and pre-eclampsia
are associated with a greater degree of trophoblast hypoxia. The metabolic activity of placental mitochondria leads to oxidative
stress even in normal pregnancy which is exacerbated further in IUGR, diabetic and pre-eclamptic pregnancies and may also
give nitrative stress known to lead to covalent modification and hence altered activity of proteins. Hypoxia, oxidative and
nitrative stress all alter placenta development and may be a general underlying mechanism that links altered placental function
to fetal programming.
Abstract Introduction Maternal obesity creates an adverse intrauterine environment, negatively impacts placental respiration, is associated with a higher incidence of pregnancy complications and ...programs the offspring for disease in adult life in a sexually dimorphic manner. We defined the effect of maternal obesity and fetal sex on pro- and anti-oxidant status in placenta and placental mitochondria. Methods: Placental villous tissue was collected at term via c-section prior to labor from four groups of patients based on fetal sex and prepregnancy/1st trimester body mass index: lean - BMI 22.1 ± 0.3 (6 male, 6 female) and obese - BMI 36.3 ± 0.4 (6 male, 6 female). Antioxidant enzyme activity, mitochondrial protein carbonyls, nitrotyrosine residues, total and nitrated superoxide dismutase (SOD) and nitric oxide synthesis were measured. Results: Maternal obesity was associated with decreased SOD and catalase activity, and total antioxidant capacity (TAC), but increased oxidative (protein carbonyls) and nitrative (nitrotyrosine) stress in a sexually dimorphic manner. Placentas of lean women with a male fetus had higher SOD activity and TAC (p < 0.05) than other groups whereas obese women with a male fetus had highest carbonyls and nitrotyrosine (p < 0.05). Glutathione peroxidase and thioredoxin reductase activity increased with obesity, significantly with a male fetus, perhaps as a compensatory response. Conclusion: Maternal obesity affects oxidative stress and antioxidant activity in the placenta in a sexually dimorphic manner. The male fetus of a lean women has the highest antioxidant activity, a protection which is lost with obesity perhaps contributing to the increased incidence of adverse outcomes with a male fetus.
In the placenta the proliferative cytotrophoblast cells fuse into the terminally differentiated syncytiotrophoblast layer which undertakes several energy-intensive functions including nutrient uptake ...and transfer and hormone synthesis. We used Seahorse glycolytic and mitochondrial stress tests on trophoblast cells isolated at term from women of healthy weight to evaluate if cytotrophoblast (CT) and syncytiotrophoblast (ST) have different bioenergetic strategies, given their different functions. Whereas there are no differences in basal glycolysis, CT have significantly greater glycolytic capacity and reserve than ST. In contrast, ST have significantly higher basal, ATP-coupled and maximal mitochondrial respiration and spare capacity than CT. Consequently, under stress conditions CT can increase energy generation via its higher glycolytic capacity whereas ST can use its higher and more efficient mitochondrial respiration capacity. We have previously shown that with adverse in utero conditions of diabetes and obesity trophoblast respiration is sexually dimorphic. We found no differences in glycolytic parameters between sexes and no difference in mitochondrial respiration parameters other than increases seen upon syncytialization appear to be greater in females. There were differences in metabolic flexibility, i.e., the ability to use glucose, glutamine, or fatty acids, seen upon syncytialization between the sexes with increased flexibility in female trophoblast suggesting a better ability to adapt to changes in nutrient supply.
Although much progress is being made in understanding the molecular pathways in the placenta that are involved in the pathophysiology of pregnancy-related disorders, a significant gap exists in the ...utilization of this information for the development of new drug therapies to improve pregnancy outcome. On March 5-6, 2015, the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health sponsored a 2-day workshop titled Placental Origins of Adverse Pregnancy Outcomes: Potential Molecular Targets to begin to address this gap. Particular emphasis was given to the identification of important molecular pathways that could serve as drug targets and the advantages and disadvantages of targeting these particular pathways. This article is a summary of the proceedings of that workshop. A broad number of topics were covered that ranged from basic placental biology to clinical trials. This included research in the basic biology of placentation, such as trophoblast migration and spiral artery remodeling, and trophoblast sensing and response to infectious and noninfectious agents. Research findings in these areas will be critical for the formulation of the development of future treatments and the development of therapies for the prevention of a number of pregnancy disorders of placental origin that include preeclampsia, fetal growth restriction, and uterine inflammation. Research was also presented that summarized ongoing clinical efforts in the United States and in Europe that has tested novel interventions for preeclampsia and fetal growth restriction, including agents such as oral arginine supplementation, sildenafil, pravastatin, gene therapy with virally delivered vascular endothelial growth factor, and oxygen supplementation therapy. Strategies were also proposed to improve fetal growth by the enhancement of nutrient transport to the fetus by modulation of their placental transporters and the targeting of placental mitochondrial dysfunction and oxidative stress to improve placental health. The roles of microRNAs and placental-derived exosomes, as well as messenger RNAs, were also discussed in the context of their use for diagnostics and as drug targets. The workshop discussed the aspect of safety and pharmacokinetic profiles of potential existing and new therapeutics that will need to be determined, especially in the context of the unique pharmacokinetic properties of pregnancy and the hurdles and pitfalls of the translation of research findings into practice. The workshop also discussed novel methods of drug delivery and targeting during pregnancy with the use of macromolecular carriers, such as nanoparticles and biopolymers, to minimize placental drug transfer and hence fetal drug exposure. In closing, a major theme that developed from the workshop was that the scientific community must change their thinking of the pregnant woman and her fetus as a vulnerable patient population for which drug development should be avoided, but rather be thought of as a deprived population in need of more effective therapeutic interventions.
Despite intensive investigation, we still cannot adequately predict, treat, or prevent preeclampsia. We have gained awareness that preeclampsia is a syndrome not a disease and is heterogeneous in its ...presentation and pathophysiology, which may indicate differing underlying phenotypes, and that the impact extends beyond pregnancy per se. Effects on the fetus and mother extend many years after pregnancy, as evidenced by fetal programming of adult disease and increased risk of the development of maternal cardiovascular disease. The increased occurrence of preeclampsia in women with preexisting risk factors suggests that the stress of pregnancy may expose subclinical vascular disease as opposed to preeclampsia damaging the vasculature. The heterogeneity of preeclampsia has blighted efforts to predict preeclampsia early in gestation and has thwarted success in attempts at therapy with treatments, such as low-dose aspirin or global antioxidants. There is a critical need to identify the phenotypes to enable their specific prediction and treatment. Such studies require considerably larger collections of patients than employed in past and current studies. This does not necessarily imply much larger patient numbers in single studies but can be facilitated by the ability to easily combine many smaller studies. This can be accomplished by agreeing on a priori standardized and harmonized clinical data and biospecimen collection across new studies. Such standards are being established by international groups of investigators. Leadership by international organizations, perhaps adopting a carrot and stick approach, to overcome investigator, institutional and funder reticence toward data sharing is required to ensure adoption of such standards. Future studies should include women in both low- and high-resource settings and employ social media and novel methods for data collection and analysis, including machine learning and artificial intelligence. The goal is to identify the pathophysiology underlying differing preeclampsia phenotypes, their successful prediction with the design, and the implementation of phenotype-specific therapies.
The inflammatory and metabolic derangements of obesity in pregnant women generate an adverse intrauterine environment, increase pregnancy complications and adverse fetal outcomes and program the ...fetus for obesity and metabolic syndrome in later life. We hypothesized that epigenetic modifications in placenta including altered DNA methylation/hydroxymethylation may mediate these effects. Term placental villous tissue was collected following cesarean section from lean (prepregnancy BMI<25) or obese (BMI>30) women. Genomic DNA was isolated, methylated and hydroxymethylated DNA immunoprecipitated and hybridized to the NimbleGen 2.1M human DNA methylation array. Intermediate metabolites in placental tissues were measured by HPLC-ESI-MS, ascorbate levels by reverse phase HPLC and gene expression by RT-PCR. Differentially methylated and hydroxymethylated regions occurred across the genome, with a 21% increase in methylated but a 31% decrease in hydroxymethylated regions in obese vs lean groups. Whereas increased methylation and decreased methylation was evident around transcription start sites of multiple genes in the GH/CSH and PSG gene clusters on chromosomes 17 and 19 in other areas there was no relationship. Increased methylation was associated with decreased expression only for some genes in these clusters. Biological pathway analysis revealed the 262 genes which showed reciprocal differential methylation/ hydroxymethylation were enriched for pregnancy, immune response and cell adhesion-linked processes. We found a negative relationship for maternal BMI but a positive relationship for ascorbate with α-ketoglutarate a metabolite that regulates ten eleven translocase (TET) which mediates DNA methylation. We provide evidence for the obese maternal metabolic milieu being linked to an altered DNA methylome that may affect placental gene expression in relation to adverse outcomes.
Trophoblast oxidative phosphorylation provides energy for active transport and protein synthesis, which are critical placental functions influencing fetal growth and long-term health. The molecular ...mechanisms regulating trophoblast mitochondrial oxidative phosphorylation are largely unknown. We hypothesized that mechanistic Target of Rapamycin Complex 1 (mTORC1) is a positive regulator of key genes encoding Electron Transport Chain (ETC) proteins and stimulates oxidative phosphorylation in trophoblast and that ETC protein expression is down-regulated in placentas of infants with intrauterine growth restriction (IUGR). We silenced raptor (mTORC1 inhibition), rictor (mTORC2 inhibition) or DEPTOR (mTORC1/2 activation) in cultured term primary human trophoblast (PHT) cells. mTORC1 inhibition caused a coordinated down-regulation of 18 genes encoding ETC proteins representing all ETC complexes. Inhibition of mTORC1, but not mTORC2, decreased protein expression of ETC complexes I-IV, mitochondrial basal, ATP coupled and maximal respiration, reserve capacity and proton leak, whereas activation of mTORC1 had the opposite effects. Moreover, placental protein expression of ETC complexes was decreased and positively correlated to mTOR signaling activity in IUGR. By controlling trophoblast ATP production, mTORC1 links nutrient and O
availability and growth factor signaling to placental function and fetal growth. Reduced placental mTOR activity may impair mitochondrial respiration and contribute to placental insufficiency in IUGR pregnancies.
The fetal membranes fulfill several functions during pregnancy. In addition to containing the products of conception and amniotic fluid, they presumably have barrier functions and fulfill paracrine ...signaling functions between the maternal (decidual) and fetal compartments. As the membranes are in an ideal place to receive both maternal and fetal signals and transmit signals to uterine myometrium, there has been a specific focus on the role of membranes in the initiation and maintenance of parturition. In this review, we summarize the data obtained in our laboratories as well as the data reported in the literature particularly with regard to the synthesis of steroids and prostaglandins in the fetal membranes, in signaling fetal maturation and in parturition. The fetal membranes are a major site both of prostaglandin synthesis and of prostaglandin metabolism. In addition, the abundant expression of 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1), which converts biologically inactive cortisone into active cortisol, in the fetal membranes may provide an extra-adrenal source of glucocorticoids for the fetal compartment during gestation. Accumulating evidence indicates that a positive feedback loop involving glucocorticoids, proinflammatory cytokines, prostaglandins, surfactant protein-A (SP-A) and 11beta-HSD1 is formed locally in human fetal membranes towards term or in preterm labor. This positive feedback loop would produce abundant biologically active glucocorticoids and prostaglandins in the fetal membranes or amniotic fluid, which would ultimately promote fetal organ maturation and initiate parturition.
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