Human Fetal Growth Research Articles

Hematopoietically expressed (HEX) gene is a transcriptional regulator of placental angiogenesis in human fetal growth restriction; altering expression of its downstream target genes may improve vascular function.

Hematopoietically expressed (HEX) gene is a transcriptional regulator of placental angiogenesis in human fetal growth restriction; altering expression of its downstream target genes may improve vascular function.

Mapping regulatory elements at the DLK1 locus involved in the pathogenesis of human fetal growth restriction

Mapping regulatory elements at the DLK1 locus involved in the pathogenesis of human fetal growth restriction

Monogenic disease analysis establishes that fetal insulin accounts for half of human fetal growth.

Monogenic disease analysis establishes that fetal insulin accounts for half of human fetal growth.

Altered Cord Blood Lipid Concentrations Correlate with Birth Weight and Doppler Velocimetry of Fetal Vessels in Human Fetal Growth Restriction Pregnancies.

Fetal growth restriction (FGR) is associated with short- and long-term morbidity, often with fetal compromise in utero, evidenced by abnormal Doppler velocimetry of fetal vessels. Lipids are vital for growth and development, but metabolism in FGR pregnancy, where fetuses do not grow to full genetic potential, is poorly understood. We hypothesize that triglyceride concentrations are increased in placentas and that important complex lipids are reduced in cord plasma from pregnancies producing the smallest babies (birth weight < 5%) and correlate with ultrasound Dopplers. Dopplers (umbilical artery, UA; middle cerebral artery, MCA) were assessed longitudinally in pregnancies diagnosed with estimated fetal weight (EFW) < 10% at ≥29 weeks gestation. For a subset of enrolled women, placentas and cord blood were collected at delivery, fatty acids were extracted and targeted lipid class analysis (triglyceride, TG; phosphatidylcholine, PC; lysophosphatidylcholine, LPC; eicosanoid) performed by LCMS. For this sub-analysis, participants were categorized as FGR (Fenton birth weight, BW ≤ 5%) or SGA “controls” (Fenton BW > 5%). FGRs (n = 8) delivered 1 week earlier (p = 0.04), were 29% smaller (p = 0.002), and had 133% higher UA pulsatility index (PI, p = 0.02) than SGAs (n = 12). FGR plasma TG, free arachidonic acid (AA), and several eicosanoids were increased (p < 0.05); docosahexaenoic acid (DHA)-LPC was decreased (p < 0.01). Plasma TG correlated inversely with BW (p < 0.05). Plasma EET, non-esterified AA, and DHA correlated inversely with BW and directly with UA PI (p < 0.05). Placental DHA-PC and AA-PC correlated directly with MCA PI (p < 0.05). In fetuses initially referred for inadequate fetal growth (EFW < 10%), those with BW ≤ 5% demonstrated distinctly different cord plasma lipid profiles than those with BW > 5%, which correlated with Doppler PIs. This provides new insights into fetal lipidomic response to the FGR in utero environment. The impact of these changes on specific processes of growth and development (particularly fetal brain) have not been elucidated, but the relationship with Doppler PI may provide additional context for FGR surveillance, and a more targeted approach to nutritional management of these infants.

The Placental NLRP3 Inflammasome and Its Downstream Targets, Caspase-1 and Interleukin-6, Are Increased in Human Fetal Growth Restriction: Implications for Aberrant Inflammation-Induced Trophoblast Dysfunction.

Fetal growth restriction (FGR) is commonly associated with placental insufficiency and inflammation. Nonetheless, the role played by inflammasomes in the pathogenesis of FGR is poorly understood. We hypothesised that placental inflammasomes are differentially expressed and contribute to the aberrant trophoblast function. Inflammasome gene expression profiles were characterised by real-time PCR on human placental tissues collected from third trimester FGR and gestation-matched control pregnancies (n = 25/group). The functional significance of a candidate inflammasome was then investigated using lipopolysaccharide (LPS)-induced models of inflammation in human trophoblast organoids, BeWo cells in vitro, and a murine model of FGR in vivo. Placental mRNA expression of NLRP3, caspases 1, 3, and 8, and interleukin 6 increased (>2-fold), while that of the anti-inflammatory cytokine, IL-10, decreased (<2-fold) in FGR compared with control pregnancies. LPS treatment increased NLRP3 and caspase-1 expression (>2-fold) in trophoblast organoids and BeWo cell cultures in vitro, and in the spongiotrophoblast and labyrinth in the murine model of FGR. However, the LPS-induced rise in NLRP3 was attenuated by its siRNA-induced down-regulation in BeWo cell cultures, which correlated with reduced activity of the apoptotic markers, caspase-3 and 8, compared to the control siRNA-treated cells. Our findings support the role of the NLRP3 inflammasome in the inflammation-induced aberrant trophoblast function, which may contribute to FGR.

Urinary Concentrations of Bisphenol Mixtures during Pregnancy and Birth Outcomes: The MAKE Study.

Bisphenols are endocrine disruptors that may be associated with altered fetal growth in humans, and they have similar biological functions to mimic hormones. In addition, aggregated chemicals showed an adverse effect although individual concentration was at a low level. However, most studies between bisphenols and birth outcomes have focused on the effect of individual bisphenol. Thus, we explored the associations of urinary bisphenol mixtures with birth outcomes. We conducted a prospective birth cohort study in South Korea. One hundred eighty mother-infant pairs were recruited from 2017 to 2019. Bisphenol A (BPA), bisphenol F (BPF), and bisphenol S (BPS) in one spot urine were analyzed using ultra-performance liquid chromatography–tandem mass spectrometry. We used two statistical approaches to examine potential associations of BPA, BPF, and BPS with birth weight and gestational age: (1) multivariable linear regression; (2) Bayesian kernel machine regression (BKMR). The geometric means of BPA, BPF, and BPS were 2.1, 0.2, and 0.1 μg/L, respectively. In stratified linear analyses by each median value, a higher BPF was positively associated with birth weight (g) (β = 125.5; 95% CI: 45.0 to 205.9). Mixture analyses using BKMR suggested an inverse association between bisphenol mixtures and birth weight. Our findings suggest that in utero bisphenol exposure may influence birth weight and that such relationships may differ considering non-linearity and the combined effect.

Decreased expression of apical-basal polarity genes SCRIBBLE and LGL2 is associated with abnormal trophoblast function: Potential implications in the aetiology of human fetal growth restriction.

Decreased expression of apical-basal polarity genes SCRIBBLE and LGL2 is associated with abnormal trophoblast function: Potential implications in the aetiology of human fetal growth restriction.

Urinary concentrations of bisphenol mixtures during pregnancy and birth outcomes: The MAKE study

BACKGROUND AND AIM: Bisphenols are endocrine disruptors that may be associated with altered fetal growth in humans. To date, most studies between bisphenols and birth outcomes have focused on the effect of individual bisphenol. The aim of this study was to explore the associations of urinary bisphenol mixtures with birth outcomes. METHODS: We conducted a prospective birth cohort study in South Korea. One hundred eighty mother-infant pairs were recruited from 2017 to 2019. Bisphenol A (BPA), bisphenol F (BPF), and bisphenol S (BPS) in one spot urine were analyzed using ultra-performance liquid chromatography–tandem mass spectrometry. We used two statistical approaches to examine potential associations of BPA, BPF, and BPS with birth weight and gestational age: 1) multivariable linear regression; 2) Bayesian kernel machine regression (BKMR). RESULTS:The geometric means of BPA, BPF, and BPS were 2.1, 0.2, and 0.1 μg/L, respectively. In stratified linear analyses by each median value, a higher BPF was positively associated with birth weight (g) (β = 125.5; 95% CI: 45.0 to 205.9). Mixture analyses using BKMR suggested an inverse association between bisphenol mixtures and birth weight. CONCLUSIONS:Our findings suggest that in utero bisphenol exposure may influence birth weight and that such relationships may differ considering non-linearity and the combined effect. KEYWORDS: Phenols, Birth outcomes, Mixtures analysis, Environmental epidemiology

164-LB: Association of Maternal Insulin Sensitivity during Gestation and Neonatal Size

Background: Decrease in insulin sensitivity in late gestation is thought to promote fetal growth in humans. Methods: Cohorts with serial glucose and insulin measurements during pregnancy were included in this study. These include two Indian (n=248), a Mexican (n=115), two European (n=326) and an American (n=32) cohort. HOMA-S was correlated with neonatal weight. Results: Indian mothers were short & thin (153.7 cm, 48.8 kg and 20.2 kg/m2) and gained 5.9 kg between first and third trimesters, babies were 2720g. Mexican mothers were short (156cm, 63 kg and BMI 25.1kg/m2) and gained 7.5 kg, babies were 2955g. European mothers were tall and obese (168.0 cm, 95.5 kg and 33.7 kg/m2), gained 7.4 kg and babies were 3640g. In Indian mothers, FPG progressively decreased with increasing gestation with a small (15%) increase in insulin concentrations, HOMA-S remained stable. In Mexican and European mothers FPG remained stable, insulin increased (>50%) and HOMA-S decreased (>30%). American mothers showed the classic increase in HOMA-S in early pregnancy and a fall in late gestation (Figure 1). In Indian and Mexican mothers HOMA-S was not associated with offspring birth weight while in European cohorts, it was inversely associated. Conclusion: Chronic maternal undernutrition (stunting) and failure to reduce insulin sensitivity in late gestation may contribute to poor fetal growth in India and Mexico. Mechanistic studies are warranted. Disclosure S. Deshpande-joshi: None. O. Perichart-perera: Other Relationship; Self; IFA CELTICS, Nestle. M. Van poppel: None. C. A. Vinter: None. D. M. Jensen: None. G. Desoye: None. P. Catalano: None. C. S. Yajnik: None. H. Damle: None. M. K. Deshmukh: None. D. Bhat: None. N. S. Memane: None. A. A. Bhalerao: None. R. Ladkat: None. P. Tiwari: None. S. R. Otiv: None.

A 3D analysis of growth trajectory and integration during early human prenatal facial growth

Significant shape changes in the human facial skeleton occur in the early prenatal period, and understanding this process is critical for studying a myriad of congenital facial anomalies. However, quantifying and visualizing human fetal facial growth has been challenging. Here, we applied quantitative geometric morphometrics (GM) to high-resolution magnetic resonance images of human embryo and fetuses, to comprehensively analyze facial growth. We utilized non-linear growth estimation and GM methods to assess integrated epigenetic growth between masticatory muscles and associated bones. Our results show that the growth trajectory of the human face in the early prenatal period follows a curved line with three flexion points. Significant antero-posterior development occurs early, resulting in a shift from a mandibular prognathic to relatively orthognathic appearance, followed by expansion in the lateral direction. Furthermore, during this time, the development of the zygoma and the mandibular ramus is closely integrated with the masseter muscle.

Radial glomerular count- An assessment of human nephrogenesis

Introduction: The important reason for progression of various glomerulopathies is variable Radial glomerular count [RGC]. There are few studies on the radial glomerular count. Therefore, we conduct this study, with an aim to contribute the knowledge of the human developing kidney by counting radial glomerular number. Materials and Methods: Thirty normal human fetuses of midgestational period [14 to 28 weeks] were selected for the study. The fetus should not have any congenital anomaly. The fetal kidney tissue slides were prepared and stained in hematoxylin and eosin. Then numbers of glomerular generations were counted and correlate the data with the different gestational groups. Results: The results showed that the average RGC is gradually increasing from 4 to 15 counts in mid gestational age. The results suggest significant statistical correlation between the period of gestation and the number of glomerular generations (Correlation coefficient value R2= 0.99). The fetal kidney weight and the number of glomerular generations in respective gestational age also shows definite statistical correlations. Conclusion: The present study concluded that gradually increasing average RGC can express human fetal kidney growth in intrauterine life. The histomorphologic assessment of RGC can be used as relatively better method of estimating gestational age. The observed growth tendencies of fetal glomerulus in human fetal life by RGC could be useful to assess the kidney maturity in the future. Keywords: Glomerulopathies, RGC.

Endocrine-Disrupting Chemicals in Human Fetal Growth.

Fetal growth is regulated by a complex interaction of maternal, placental, and fetal factors. The effects and outcomes that chemicals, widely distributed in the environment, may have on the health status of both the mother and the fetus are not yet well defined. Mainly mixtures of chemical substances are found in the mothers and placenta. Exposure to endocrine-disrupting chemicals (EDCs) can be associated with fetal growth retardation, thyroid dysfunction, and neurological disorders. EDCs mostly interfere with insulin, glucocorticoid, estrogenic, and thyroid pathways, with subsequent effects on normal endocrine and metabolic functions, which cause changes in the epigenome and state of inflammation with life-long effects and consequences. International scientific societies recommend the implementation of research and of all possible preventive measures. This review briefly summarizes all these aspects.

Association of Prenatal Maternal Psychological Distress With Fetal Brain Growth, Metabolism, and Cortical Maturation

Prenatal maternal stress is increasingly associated with adverse outcomes in pregnant women and their offspring. However, the association between maternal stress and human fetal brain growth and metabolism is unknown. To identify the association between prenatal maternal psychological distress and fetal brain growth, cortical maturation, and biochemical development using advanced 3-dimensional volumetric magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1H-MRS). This cohort study prospectively recruited pregnant women from low-risk obstetric clinics in Washington, DC, from January 1, 2016, to April 17, 2019. Participants were healthy volunteers with a normal prenatal medical history, no chronic or pregnancy-induced physical or mental illnesses, and normal results on fetal ultrasonography and biometry studies. Fetal brain MRI studies were performed at 2 time points between 24 and 40 weeks' gestation. Prenatal maternal stress, anxiety, and depression. Volumes of fetal total brain, cortical gray matter, white matter, deep gray matter, cerebellum, brainstem, and hippocampus were measured from 3-dimensional reconstructed T2-weighted MRI scans. Cortical folding measurements included local gyrification index, sulcal depth, and curvedness. Fetal brain N-acetylaspartate, creatine, and choline levels were quantified using 1H-MRS. Maternal stress, depression, and anxiety were measured with the Perceived Stress Scale (PSS), Edinburgh Postnatal Depression Scale (EPDS), Spielberger State Anxiety Inventory (SSAI), and Spielberger Trait Anxiety Inventory (STAI). A total of 193 MRI studies were performed in 119 pregnant women (67 [56%] carrying male fetuses and 52 [44%], female fetuses; maternal mean [SD] age, 34.46 [5.95] years) between 24 and 40 gestational weeks. All women were high school graduates, 99 (83%) were college graduates, and 100 (84%) reported professional employment. Thirty-two women (27%) had positive scores for stress, 31 (26%) for anxiety, and 13 (11%) for depression. Maternal trait anxiety was associated with smaller fetal left hippocampal volume (STAI score: -0.002 cm3; 95% CI, -0.003 to -0.0008 cm3; P = .004). Maternal anxiety and stress were associated with increased fetal cortical gyrification in the frontal lobe (β for SSAI score: 0.004 [95% CI, 0.001-0.006; P = .002]; β for STAI score: 0.004 [95% CI, 0.002-0.006; P < .001]; β for PSS score: 0.005 [95% CI, 0.001-0.008; P = .005]) and temporal lobe (β for SSAI score: 0.004 [95% CI, 0.001-0.007; P = .004]; β for STAI score: 0.004 [95% CI, 0.0008-0.006; P = .01]). Elevated maternal depression was associated with decreased creatine (EPDS score: -0.04; 95% CI, -0.06 to -0.02; P = .005) and choline (EPDS score: -0.03; 95% CI, -0.05 to -0.01; P = .02) levels in the fetal brain. This study found that the prevalence of maternal psychological distress in healthy, well-educated, and employed pregnant women was high, underappreciated, and associated with impaired fetal brain biochemistry and hippocampal growth as well as accelerated cortical folding. These findings appear to support the need for routine mental health surveillance for all pregnant women and targeted interventions in women with elevated psychological distress.

Whole-transcriptome sequencing uncovers core regulatory modules and gene signatures of human fetal growth restriction

BackgroundFetal growth restriction (FGR) contributes the primary cause of perinatal mortality and morbidity with impacts on the long-term health. To determine the core gene expression network and gene signatures, which in combination with ultrasound confirmation will more effectively differentiate constitutionally normal small for gestational age and pathological FGR groups, we performed RNA sequencing for protein-coding genes, lncRNAs, and small RNAs in a case–control study of umbilical cord blood.ResultsFive pairs of FGR case and control umbilical cord blood samples were used for RNA sequencing and weighted gene co-expression network analysis (WGCNA). Results showed that 339 mRNAs, 295 lncRNAs, and 13 miRNAs were significantly differentially expressed between FGR cases and controls. Bioinformatics analysis indicated that these differentially expressed molecules were mainly involved in metabolism, neural, cardiac, and immune systems, and identified 18 WGCNA modules for FGR. Further quantitative verification was performed using umbilical cord blood and maternal peripheral blood from 12 pairs of FGR cases and controls. The logistic regression and receiver operating characteristic curve indicated that RP11_552M6.1, LINC01291, and Asgr1 in umbilical cord blood, while Sfrp2, miR-432-5p, and miR-1306-3p in maternal peripheral blood had potential significance for FGR.ConclusionsWe comprehensively profiled the whole-transcriptome landscape of human umbilical cord blood with FGR, constructed the core WGCNA modules, and delineated the critical gene signatures of FGR. These findings provide key insight into intrauterine perturbations and candidate signatures for FGR.

132 Introduction of F508del human mutation into the CFTR gene of sheep fetal fibroblasts using CRISPR/Cas9 ribonucleoprotein

Cystic fibrosis (CF) is an autosomal recessive genetic disease that affects over 30 000 people in the United States and is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The CFTR protein is a cAMP-regulated C− channel responsible for regulation of anion transport, primarily in the epithelial cells. We have previously generated a sheep model of CF by genetically inactivating the CFTR gene (Fan et al. 2018 JCI Insight 3, e123529). The newborn CFTR −/− sheep develops severe disease consistent with CF pathology in humans. The CF model is extremely valuable for understanding the developmental aspects of CF disease, as sheep have been used extensively in the study of human fetal growth and development. Sheep, like humans, typically give birth to only one or two offspring in each pregnancy, which make them more suitable than many other species for testing prenatal gene-editing treatments. Thus, in this new study, we are working on the generation of F508del sheep CF model. The F508del mutation was chosen because it is the most common mutation in the human CFTR gene (~70%). This mutation is characterised by the deletion of the CTT nucleotides, which ultimately deletes the phenylalanine residue at position 508. The F508del mutation causes misfolding of the CFTR protein, which is further degraded by proteases. Even though several CFTR modulators are available, they are not effective in all patients. Additionally, they cannot reverse deleterious prenatal CF manifestations. Hence, this model will be valuable for evaluating both prenatal drug and gene therapies. Here, we used a CRISPR/Cas9 gene-editing approach to introduce the F508del mutation into the sheep genome. We designed an sgRNA targeting exon 11 of the sheep CFTR gene using the Benchling software (https://benchling.com/academic). The sgRNA was synthesised by Synthego and Cas9 purchased from ThermoFisher. Using the Lonza-4D-Nucleofector system, Cas9/sgRNA ribonucleoprotein complex was transfected into sheep fetal fibroblasts (SFFs), along with 100bp single-stranded oligodeoxynucleotide, flanking the F508del mutation, for the homology-directed repair. The transfected cells were subsequently cultured in Dulbecco's modified Eagle's medium, supplemented with 15% fetal bovine serum and 1% penicillin, and incubated at 38.5°C. Two days post-transfection, SFFs were seeded individually into five 96-well plates by limited dilution. After seven days, the individual colonies were expanded into 24-well plates and cultured for three more days. A total of 56 single-cell-derived SFF colonies were isolated. The presence of F508del mutation was confirmed by amplifying the PCR products of the exon 11 flanking the mutation site and subjecting each amplicon to Sanger sequencing. The sequencing results indicated that the indels (insertion/deletion) were introduced in 49 out of 56 (87.5%) of the colonies, and four (7.14%) of them were confirmed to have biallelic F508del mutations based on sequencing peaks. Therefore, we successfully introduced the F508del mutation in SFFs that will be used for the production of F508del CF sheep by somatic cell nuclear transfer.

Associations of Trimester-Specific Exposure to Bisphenols with Size at Birth: A Chinese Prenatal Cohort Study.

Background:Bisphenol A (BPA) is an endocrine disruptor that affects fetal growth in experimental studies. Bisphenol F (BPF) and bisphenol S (BPS), which have been substituted for BPA in some consumer products, have also shown endocrine-disrupting effects in experimental models. However, the effects of BPF and BPS on fetal growth in humans are unknown.Objectives:Our goal was to investigate trimester-specific associations of urinary concentrations of BPA, BPF, and BPS with size at birth.Methods:The present study included 845 pregnant women from Wuhan, China (2013–2015), who provided one urine sample in each of the first, second, and third trimesters. Linear regressions with generalized estimating equations were applied to estimate trimester-specific associations of urinary bisphenol concentrations with birth weight, birth length, and ponderal index. Linear mixed-effects models were used to identify potential critical windows of susceptibility to bisphenols by comparing the exposure patterns of newborns in the 10th percentile of each birth anthropometric measurement to that of those in the 90th percentile.Results:Medians (25th–75th percentiles) of urinary concentrations of BPA, BPF, and BPS were 1.40 (0.19–3.85), 0.65 (0.34–1.39), and 0.38 (0.13–1.11) ng/mL, respectively. Urinary BPA concentrations in different trimesters were inversely, but not significantly, associated with birth weight and ponderal index. Urinary concentrations of BPF and BPS during some trimesters were associated with significantly lower birth weight, birth length, or ponderal index, with significant trend p-values () across quartiles of BPF and BPS concentrations. The observed associations were unchanged after additionally adjusting for other bisphenols. In addition, newborns in the 10th percentile of each birth anthropometry measure had higher BPF and BPS exposures during pregnancy than newborns in the 90th percentile of each outcome.Conclusions:Prenatal exposure to BPF and BPS was inversely associated with size at birth in this cohort. Replication in other populations is needed. https://doi.org/10.1289/EHP4664

OC15.06: Human fetal growth restriction is influenced mainly by maternal socioeconomic status: an ecological study within a city from a developing country

OC15.06: Human fetal growth restriction is influenced mainly by maternal socioeconomic status: an ecological study within a city from a developing country

Dysregulation of the placental renin-angiotensin system in human fetal growth restriction.

Fetal growth restriction (FGR) is a pregnancy complication wherein the foetus fails to reach its growth potential. The renin-angiotensin system (RAS) is a critical regulator of placental function, controlling trophoblast proliferation, angiogenesis and blood flow. The RAS significantly influences uteroplacental blood flow through the balance of its vasoconstrictive and vasodilatory pathways. Although the RAS is known to be dysregulated in placentae from women with preeclampsia, the expression of the RAS has not yet been studied in pregnancies compromised by FGR alone. This study investigated the mRNA expression and protein levels of RAS components in placentae from pregnancies compromised by FGR. Angiotensin II type 1 receptor (AGTR1) and angiotensin-converting enzyme 2 (ACE2) mRNA levels were reduced in FGR placentae compared with control (P = 0.012 and 0.018 respectively). Neprilysin (NEP) mRNA expression was lower in FGR placentae compared with control (P = 0.004). mRNA levels of angiotensinogen (AGT) tended to be higher in FGR placentae compared with control (P = 0.090). Expression of prorenin, AGT, angiotensin-converting enzyme (ACE) or ACE2 proteins were similar in control and FGR placentae. The renin-AGT reaction is a first order reaction so levels of expression of placental AGT determine levels of Ang II. Decreasing levels of ACE2 and/or NEP by limiting the production of Ang-(1-7), which is a vasodilator, and increasing placental Ang II levels (vasoconstrictor) may result in an imbalance between the vasoconstrictor and vasodilator arms of the placental RAS. Ultimately this dysregulation of the placental RAS could lead to reduced placental perfusion that is evident in FGR.

Disrupted placental serotonin synthetic pathway and increased placental serotonin: Potential implications in the pathogenesis of human fetal growth restriction

ObjectivesPlacental insufficiency contributes to altered maternal-fetal amino acid transfer, and thereby to poor fetal growth. An important placental function is the uptake of tryptophan and its metabolism to serotonin (5-HT) and kynurenine metabolites, which are essential for fetal development. We hypothesised that placental 5-HT content will be increased in pregnancies affected with fetal growth restriction (FGR). MethodsThe components of the 5-HT synthetic pathway were determined in chorionic villus samples (CVS) from small-for gestation (SGA) and matched control collected at 10–12 weeks of human pregnancy; and in placentae from third trimester FGR and gestation-matched control pregnancies using the Fluidigm Biomarker array for mRNA expression, the activity of the enzyme TPH and 5-HT concentrations using an ELISA. ResultsGene expression for the rate limiting enzymes, TPH1 and TPH2; 5-HT transporter, SLC6A4; and 5-HT receptors HTR5A, HTR5B, HTR1D and HTR1E were detected in all CVS and third trimester placentae. No significant difference in mRNA was observed in SGA compared with control. Although there was no significant change in TPH1 mRNA, the mRNA of TPH2 and SLC6A4 was significantly decreased in FGR placentae (p < 0.05), while 5-HT receptor mRNA was significantly increased in FGR compared with control (p < 0.01). Placental TPH enzyme activity was significantly increased with a concomitant increase in the total placental 5-HT concentrations in FGR compared with control. ConclusionThis study reports differential expression and activity of the key components of the 5-HT synthetic pathway associated with the pathogenesis of FGR. Further studies are required to elucidate the functional consequences of increased placental 5-HT in FGR pregnancies.

Nutrient sensor signaling pathways and cellular stress in fetal growth restriction.

Fetal growth restriction is one of the most common obstetrical complications resulting in significant perinatal morbidity and mortality. The most frequent etiology of human singleton fetal growth restriction is placental insufficiency, which occurs secondary to reduced utero-placental perfusion, abnormal placentation, impaired trophoblast invasion and spiral artery remodeling, resulting in altered nutrient and oxygen transport. Two nutrient-sensing proteins involved in placental development and glucose and amino acid transport are mechanistic target of rapamycin (mTOR) and O-linked N-acetylglucosamine transferase (OGT), which are both regulated by availability of oxygen. Impairment in either of these pathways is associated with fetal growth restriction and accompanied by cellular stress in the forms of hypoxia, oxidative and endoplasmic reticulum (ER) stress, metabolic dysfunction and nutrient starvation in the placenta. Recent evidence has emerged regarding the potential impact of nutrient sensors on fetal stress response, which occurs in a sexual dysmorphic manner, indicating a potential element of genetic gender susceptibility to fetal growth restriction. In this mini review, we focus on the known role of mTOR and OGT in placental development, nutrient regulation and response to cellular stress in human fetal growth restriction with supporting evidence from rodent models.