Placental FKBP51 mediates a link between second trimester maternal anxiety and birthweight in female infants.
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ABSTRACT:
SUBMITTER: Togher KL
PROVIDER: S-EPMC6181924 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundPlacental Plasmodium falciparum malaria can trigger intervillositis, a local inflammatory response more strongly associated with low birthweight than placental malaria infection alone. Fetal growth (and therefore birthweight) is dependent on placental amino acid transport, which is impaired in placental malaria-associated intervillositis. Here, we tested the hypothesis that mechanistic target of rapamycin (mTOR) signaling, a pathway known to regulate amino acid transport, is inhibited in placental malaria-associated intervillositis, contributing to lower birthweight.MethodsWe determined the link between intervillositis, mTOR signaling activity, and amino acid uptake in tissue biopsies from both uninfected placentas and malaria-infected placentas with and without intervillositis, and in an in vitro model using primary human trophoblast (PHT) cells.ResultsWe demonstrated that (1) placental mTOR activity is lower in cases of placental malaria with intervillositis, (2) placental mTOR activity is negatively correlated with the degree of inflammation, and (3) inhibition of placental mTOR activity is associated with reduced placental amino acid uptake and lower birthweight. In PHT cells, we showed that (1) inhibition of mTOR signaling is a mechanistic link between placental malaria-associated intervillositis and decreased amino acid uptake and (2) constitutive mTOR activation partially restores amino acid uptake.ConclusionsOur data support the concept that inhibition of placental mTOR signaling constitutes a mechanistic link between placental malaria-associated intervillositis and decreased amino acid uptake, which may contribute to lower birthweight. Restoring placental mTOR signaling in placental malaria may increase birthweight and improve neonatal survival, representing a new potential therapeutic approach.
| S-EPMC5209943 | biostudies-literature
Project description:ObjectiveWe hypothesized that the origins of abruption may extend to the stages of placental implantation; however, there are no reliable markers to predict its development. Based on this hypothesis, we sought to evaluate whether first-trimester and second-trimester serum analytes predict placental abruption.MethodsWe performed a secondary analysis of data of 35,307 women (250 abruption cases) enrolled in the First and Second Trimester Evaluation of Risk cohort (1999-2003), a multicenter, prospective cohort study. Percentiles (based on multiples of the median) of first-trimester (pregnancy-associated plasma protein A and total and free β-hCG) and second-trimester (maternal serum alpha-fetoprotein, unconjugated estriol, and inhibin-A) serum analytes were examined in relation to abruption. Associations are based on risk ratio (RR) and 95% confidence interval (CI).ResultsWomen with an abnormally low pregnancy-associated plasma protein A (fifth percentile or less) were at increased risk of abruption compared with those without abruption (9.6% compared with 5.3%; RR 1.9, 95% CI, 1.2-2.8). Maternal serum alpha-fetoprotein 95th percentile or greater was more common among abruption (9.6%) than nonabruption (5.1%) pregnancies (RR 1.9, 95% CI 1.3-3.0). Inhibin-A fifth percentile or less (8.0% compared with 5.1%; RR 1.8, 95% CI 1.1-2.9), and 95th percentile or greater (9.6% compared with 5.0%; RR 2.0, 95% CI 1.3-3.1) were associated with abruption. Women with all three abnormal pregnancy-associated plasma protein A, maternal serum alpha-fetoprotein, and inhibin-A analytes were at 8.8-fold (95% CI 2.3-34.3) risk of abruption. No associations were seen with other analytes.ConclusionThese data provide support for our hypothesis that the origins of placental abruption may extend to the early stages of pregnancy.
| S-EPMC5367463 | biostudies-literature
Project description:ObjectiveThe aim of the study was to evaluate the diagnostic potential of placental shear wave elastography in predicting preeclampsia at 16 to 20 weeks of gestation.Materials and methodsA total of 230 pregnant women between 16 and 20 weeks of gestation were observed for the study. These women underwent shear wave elastography ElastPQ (Philips Healthcare, Bothell, Washington, USA) of the placenta. The mean value of placental shear modulus was obtained for each participant. These participants were followed up for the development of preeclampsia and were divided into two groups; group A included those who developed preeclampsia and group B included those who remained normotensive until delivery. The elasticity values of the two groups were compared, and the ROC curve was drawn to obtain the best cut-off value that would predict the onset of preeclampsia.ResultsPlacental shear modulus varied from 1.03 kPa to 7.4 kPa at 16 to 20 weeks of gestation with an average of 2.74 ± 0.87 kPa. There was a statistically significant difference in the mean value of elasticity between two groups, being 4.61 kPa in group A and 2.51 kPa in group B. Maximum diagnostic accuracy was obtained at 2.9667 kPa with area under the curve 0.970, sensitivity 92%, specificity 91.71%, positive predictive value 57.5% and negative predictive value 98.9%.ConclusionStiffness of placenta, quantitatively measured by SWE at 16 to 20 weeks of gestation, is higher in the women who develop preeclampsia and hence may be used for predicting preeclampsia.
| S-EPMC9354178 | biostudies-literature
Project description:BackgroundFetal growth restriction (FGR) due to placental insufficiency is a major risk factor for stillbirth. While small-for-gestational-age (SGA; weight < 10th centile) is a commonly used proxy for FGR, detection of FGR among appropriate-for-gestational-age (AGA; weight ≥ 10th centile) fetuses remains an unmet need in clinical care. We aimed to determine whether reduced antenatal growth velocity from the time of routine mid-trimester ultrasound is associated with antenatal, intrapartum and postnatal indicators of placental insufficiency among term AGA infants.MethodsThree hundred and five women had biometry measurements recorded from their routine mid-trimester (20-week) ultrasound, at 28 and 36 weeks' gestation, and delivered an AGA infant. Mid-trimester, 28- and 36-week estimated fetal weight (EFW) and abdominal circumference (AC) centiles were calculated. The EFW and AC growth velocities between 20 and 28 weeks, and 20-36 weeks, were examined as predictors of four clinical indicators of placental insufficiency: (i) low 36-week cerebroplacental ratio (CPR; CPR < 5th centile reflects cerebral redistribution-a fetal adaptation to hypoxia), (ii) neonatal acidosis (umbilical artery pH < 7.15) after the hypoxic challenge of labour, (iii) low neonatal body fat percentage (BF%) reflecting reduced nutritional reserve and (iv) placental weight < 10th centile.ResultsDeclining 20-36-week fetal growth velocity was associated with all indicators of placental insufficiency. Each one centile reduction in EFW between 20 and 36 weeks increased the odds of cerebral redistribution by 2.5% (odds ratio (OR) = 1.025, P = 0.001), the odds of neonatal acidosis by 2.7% (OR = 1.027, P = 0.002) and the odds of a < 10th centile placenta by 3.0% (OR = 1.030, P < 0.0001). Each one centile reduction in AC between 20 and 36 weeks increased the odds of neonatal acidosis by 3.1% (OR = 1.031, P = 0.0005), the odds of low neonatal BF% by 2.8% (OR = 1.028, P = 0.04) and the odds of placenta < 10th centile by 2.1% (OR = 1.021, P = 0.0004). Falls in EFW or AC of > 30 centiles between 20 and 36 weeks were associated with two-threefold increased relative risks of these indicators of placental insufficiency, while low 20-28-week growth velocities were not.ConclusionsReduced growth velocity between 20 and 36 weeks among AGA fetuses is associated with antenatal, intrapartum and postnatal indicators of placental insufficiency. These fetuses potentially represent an important, under-recognised cohort at increased risk of stillbirth. Encouragingly, this novel fetal assessment would require only one additional ultrasound to current routine care, and adds to the potential benefits of routine 36-week ultrasound.
| S-EPMC7758928 | biostudies-literature
Project description:ObjectiveThe objective of the study was to combine early, direct assessment of the placenta with indirect markers of placental development to identify pregnancies at greatest risk of delivering small-for-gestational age infants (SGA10).Study designWe prospectively collected 3-dimensional ultrasound volume sets, uterine artery pulsatility index, and maternal serum of singleton pregnancies at 11-14 weeks. Placental volume (PV), quotient (placental quotient [PQ] = PV/gestational age), mean placental diameter (MPD) and chorionic diameters, and the placental morphology index (PMI = MPD/PQ and adjusts the lateral placental dimensions for quotient) were measured offline. Maternal serum was assayed for placental growth factor and placental protein-13. These variables were evaluated as predictors of SGA10.ResultsOf the 578 pregnancies included in the study, 56 (9.7%) delivered SGA10. SGA10 pregnancies had a significantly smaller PV, PQ, MPD, and mean placental diameter and higher PMI compared with normal pregnancies (P < .001 for each). Each placental measure remained significantly associated with SGA10 after adjusting for confounders and significantly improved the performance of the model using clinical variables alone (P < .04 for each) with adjusted areas under the curve ranging from 0.71 to 0.74. Uterine artery pulsatility index did not remain significantly associated with SGA10 after adjusting for confounders (P = .06). Placental growth factor was significantly lower in SGA10 pregnancies (P = .02) and remained significant in adjusted models but failed to significantly improve the predictive performance of the models as measured by area under the curve (P > .3). Placental protein-13 was not associated with SGA10 (P = .99).ConclusionDirect assessment of placental size and shape with 3-dimensional ultrasound can serve as the foundation upon which to build a multivariable model for the early prediction of SGA.
| S-EPMC4149853 | biostudies-literature
Project description:BackgroundInflammation is a potential risk factor of mental disturbance. FKBP5 that encodes FK506-binding protein 51 (FKBP51), a negative cochaperone of glucocorticoid receptor (GR), is a stress-inducible gene and has been linked to psychiatric disorders. Yet, the role of FKBP51 in the inflammatory stress-associated mental disturbance remained unclear.MethodsFkbp5-deficient (Fkbp5-KO) mice were used to study inflammatory stress by a single intraperitoneal injection of lipopolysaccharide (LPS). The anxiety-like behaviors, neuroimaging, immunofluorescence staining, immunohistochemistry, protein and mRNA expression analysis of inflammation- and neurotransmission-related mediators were evaluated. A dexamethasone drinking model was also applied to examine the effect of Fkbp5-KO in glucocorticoid-induced stress.ResultsLPS administration induced FKBP51 elevation in the liver and hippocampus accompanied with transient sickness. Notably, Fkbp5-KO but not wild-type (WT) mice showed anxiety-like behaviors 7 days after LPS injection (LPS-D7). LPS challenge rapidly increased peripheral and central immune responses and hippocampal microglial activation followed by a delayed GR upregulation on LPS-D7, and these effects were attenuated in Fkbp5-KO mice. Whole-brain [18F]-FEPPA neuroimaging, which target translocator protein (TSPO) to indicate neuroinflammation, showed that Fkbp5-KO reduced LPS-induced neuroinflammation in various brain regions including hippocampus. Interestingly, LPS elevated glutamic acid decarboxylase 65 (GAD65), the membrane-associated GABA-synthesizing enzyme, in the hippocampus of WT but not Fkbp5-KO mice on LPS-D7. This FKBP51-dependent GAD65 upregulation was observed in the ventral hippocampal CA1 accompanied by the reduction of c-Fos-indicated neuronal activity, whereas both GAD65 and neuronal activity were reduced in dorsal CA1 in a FKBP51-independent manner. GC-induced anxiety was also examined, which was attenuated in Fkbp5-KO and hippocampal GAD65 expression was unaffected.ConclusionsThese results suggest that FKBP51/FKBP5 is involved in the systemic inflammation-induced neuroinflammation and hippocampal GR activation, which may contribute to the enhancement of GAD65 expression for GABA synthesis in the ventral hippocampus, thereby facilitating resilience to inflammation-induced anxiety.
| S-EPMC9198626 | biostudies-literature
Project description:The human placenta is exposed to major environmental changes towards the end of the first trimester associated with full onset of the maternal arterial placental circulation. Changes include a switch from histotrophic to hemotrophic nutrition, and a threefold rise in the intraplacental oxygen concentration. We evaluated their impact on trophoblast development and function using RNA-sequencing (RNA-Seq) and DNA-methylation analyses performed on the same chorionic villous samples at 7-8 (n=8) and 13-14 (n=6) weeks of gestation. Reads were adjusted for fetal sex. Most DEGs were associated with protein processing in the endoplasmic reticulum (ER), hormone secretion, transport, extracellular matrix, vasculogenesis, and reactive oxygen species metabolism. Transcripts higher in the first trimester were associated with synthesis and ER processing of peptide hormones, and glycolytic pathways. Transcripts encoding proteins mediating transport of oxygen, lipids, protein, glucose, and ions were significantly increased in the second trimester. The motifs of CBX3 and BCL6 were significantly overrepresented, indicating the involvement of these transcription factor networks in the regulation of trophoblast migration, proliferation and fusion. These findings are consistent with a high level of cell proliferation and hormone secretion by the early placenta to secure implantation in a physiological low-oxygen environment.
| S-EPMC8214423 | biostudies-literature
Project description:Bisphenol A (BPA) is an endocrine disrupting chemical with ubiquitous environmental exposure. Animal studies have demonstrated that in utero BPA exposure leads to increased adult body weight. Our aim was to characterize human fetal BPA exposure by measuring BPA concentration in second trimester amniotic fluid (AF) samples and to study its relationship with birth weight (BW) in full term infants. To achieve these goals, we developed a total BPA assay utilizing derivatization with pentafluorobenzyl followed by analysis with LC-ECAPCI-MS/MS with a limit of detection of 0.08ng/mL and limit of quantification (LOQ) of 0.25ng/mL. The mean BW of infants with AF BPA 0.40-2.0ng/mL was 241.8g less than infants with AF BPA less than the LOQ after controlling for covariates (p=0.049). No effect was seen outside this range indicating a non-monotonic effect. Our data suggest that low level BPA exposure in utero decreases BW and needs further study.
| S-EPMC5303174 | biostudies-literature
Project description:Background: Second-trimester uterine artery Doppler is a well-established tool for the prediction of preeclampsia and fetal growth restriction. At delivery, placentas from affected pregnancies may have gross pathologic findings. Some of these features are detectable by ultrasound, but the relative importance of placental morphologic assessment and uterine artery Doppler in mid-pregnancy is presently unclear. Objective: To characterize the association of second-trimester sonographic placental morphology markers with placenta-mediated complications and determine whether these markers are predictive of placental dysfunction independent of uterine artery Doppler. Methods: This was a retrospective cohort study of patients with a singleton pregnancy at high risk of placental complications who underwent a sonographic placental study at mid-gestation (160/7−246/7 weeks’ gestation) in a single tertiary referral center between 2016–2019. The sonographic placental study included assessment of placental dimensions (length, width, and thickness), placental texture appearance, umbilical cord anatomy, and uterine artery Doppler (mean pulsatility index and early diastolic notching). Placental area and volume were calculated based on placental length, width, and thickness. Continuous placental markers were converted to multiples on medians (MoM). The primary outcome was a composite of early-onset preeclampsia and birthweight < 3rd centile. Results: A total of 429 eligible patients were identified during the study period, of whom 45 (10.5%) experienced the primary outcome. The rate of the primary outcome increased progressively with decreasing placental length, width, and area, and increased progressively with increasing mean uterine artery pulsatility index (PI). By contrast, placental thickness followed a U-shaped relationship with the primary outcome. Placental length, width, and area, mean uterine artery PI and bilateral uterine artery notching were all associated with the primary outcome. However, in the adjusted analysis, the association persisted only for placenta area (adjusted odds ratio [aOR] 0.21, 95%-confidence interval [CI] 0.06–0.73) and mean uterine artery PI (aOR 11.71, 95%-CI 3.84–35.72). The area under the ROC curve was highest for mean uterine artery PI (0.80, 95%-CI 0.71–0.89) and was significantly higher than that of placental area (0.67, 95%-CI 0.57–0.76, p = 0.44). A model that included both mean uterine artery PI and placental area did not significantly increase the area under the curve (0.82, 95%-CI 0.74–0.90, p = 0.255), and was associated with a relatively minor increase in specificity for the primary outcome compared with mean uterine artery PI alone (63% [95%-CI 58–68%] vs. 52% [95%-CI 47–57%]). Conclusion: Placental area is independently associated with the risk of placenta-mediated complications yet, when combined with uterine artery Doppler, did not further improve the prediction of such complications compared with uterine artery Doppler alone.
| S-EPMC9697802 | biostudies-literature
Project description:In response to physiological or psychological challenges, the brain activates behavioral and neuroendocrine systems linked to both metabolic and emotional outputs designed to adapt to the demand. However, dysregulation of integration of these physiological responses to challenge can have severe psychological and physiological consequences, and inappropriate regulation, disproportional intensity, or chronic or irreversible activation of the stress response is linked to the etiology and pathophysiology of mood and metabolic disorders. Using a transgenic mouse model and lentiviral approach, we demonstrate the involvement of the hypothalamic neuropeptide Urocortin-3, a specific ligand for the type-2 corticotropin-releasing factor receptor, in modulating septal and hypothalamic nuclei responsible for anxiety-like behaviors and metabolic functions, respectively. These results position Urocortin-3 as a neuromodulator linking stress-induced anxiety and energy homeostasis and pave the way toward better understanding of the mechanisms that mediate the reciprocal relationships between stress, mood and metabolic disorders.
| S-EPMC2889556 | biostudies-literature