Present views on molecular mechanisms of formation of fetal growth restriction

Fetal growth restriction (FGR) is an adverse pregnancy outcome associated with significant perinatal and paediatric morbidity and mortality, and an increased risk of chronic disease later in adult life. One of the key causes of adverse pregnancy outcome is fetal growth restriction (FGR). While a number of maternal, fetal, and environmental factors are known causes of FGR, the majority of FGR cases remain idiopathic. These idiopathic FGR pregnancies are frequently associated with placental insufficiency, possibly as a result of placental maldevelopment. Understanding the molecular mechanisms of abnormal placental development in idiopathic FGR is, therefore, of increasing importance. Here, we review our understanding of transcriptional control of normal placental development and abnormal placental development associated with human idiopathic FGR. We also assess the potential for understanding transcriptional control as a means for revealing new molecular targets for the detection, diagnosis, and clinical management of idiopathic FGR.

Download Full-text

Metallothionein-I- and -II-deficient mice display increased susceptibility to cadmium-induced fetal growth restriction

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00157.2013 ◽

2013 ◽

Vol 305 (6) ◽

pp. E727-E735 ◽

Cited By ~ 16

Author(s):

Johanna Selvaratnam ◽

Haiyan Guan ◽

James Koropatnick ◽

Kaiping Yang

Keyword(s):

Fetal Growth ◽

Fetal Growth Restriction ◽

Structural Changes ◽

Molecular Mechanisms ◽

Glucose Transporter ◽

Cadmium Exposure ◽

Growth Restriction ◽

Glut1 Expression ◽

Pregnant Mice ◽

Underlying Mechanisms

Maternal cadmium exposure induces fetal growth restriction (FGR), but the underlying mechanisms remain largely unknown. The placenta is the main organ known to protect the fetus from environmental toxins such as cadmium. In this study, we examine the role of the two key placental factors in cadmium-induced FGR. The first is placental enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which is known to protect the fetus from exposure to high cortisol levels and subsequently FGR, and the second the cadmium binding/sequestering proteins metallotheionein (MT)-I and -II. Using the MT-I/II −/− mouse model, pregnant mice were administered cadmium, following which pups and placentas were collected and examined. MT-I/II−/− pups exposed to cadmium were significantly growth restricted, but neither placental weight nor 11β-HSD2 was altered. Although cadmium administration did not result in any visible structural changes in the placenta, increased apoptosis was detected in MT-I/II−/− placentas following cadmium exposure, with a significant increase in levels of both p53 and caspase 3 proteins. Additionally, glucose transporter (GLUT1) was significantly reduced in MT-I/II−/− placentas of pups exposed to cadmium, whereas zinc transporter (ZnT-1) remained unaltered. Taken together, these results demonstrate that MT-I/II−/− mice are more vulnerable to cadmium-induced FGR. The present data also suggest that increased apoptosis and reduced GLUT1 expression in the placenta contribute to the molecular mechanisms underlying cadmium-induced FGR.

Download Full-text

Liver mTOR Controls IGF-I Bioavailability by Regulation of Protein Kinase CK2 and IGFBP-1 Phosphorylation in Fetal Growth Restriction

Endocrinology ◽

10.1210/en.2013-1759 ◽

2014 ◽

Vol 155 (4) ◽

pp. 1327-1339 ◽

Cited By ~ 23

Author(s):

Majida Abu Shehab ◽

Ian Damerill ◽

Tong Shen ◽

Fredrick J. Rosario ◽

Mark Nijland ◽

...

Keyword(s):

Fetal Growth ◽

Fetal Growth Restriction ◽

Hepg2 Cells ◽

Molecular Mechanisms ◽

Fetal Liver ◽

Growth Restriction ◽

Mtor Inhibition ◽

Site Specific ◽

Mtorc1 Signaling ◽

Igf I

Fetal growth restriction (FGR) increases the risk for perinatal complications and predisposes the infant to diabetes and cardiovascular disease later in life. No treatment for FGR is available, and the underlying pathophysiology remains poorly understood. Increased IGFBP-1 phosphorylation has been implicated as an important mechanism by which fetal growth is reduced. However, to what extent circulating IGFBP-1 is phosphorylated in FGR is unknown, and the molecular mechanisms linking FGR to IGFBP-1 phosphorylation have not been established. We used umbilical cord plasma of appropriate for gestational age (AGA) and growth–restricted human fetuses and determined IGFBP-1 and IGF-I concentrations (ELISA) and site-specific IGFBP-1 phosphorylation (Western blotting using IGFBP-1 phospho-site specific antibodies). In addition, we used a baboon model of FGR produced by 30% maternal nutrient restriction and determined mammalian target of rapamycin (mTOR)C1 activity, CK2 expression/activity, IGFBP-1 expression and phosphorylation, and IGF-I levels in baboon fetal liver by Western blot, enzymatic assay, and ELISA. HepG2 cells and primary fetal baboon hepatocytes were used to explore mechanistic links between mTORC1 signaling and IGFBP-1 phosphorylation. IGFBP-1 was hyperphosphorylated at Ser101, Ser119, and Ser169 in umbilical plasma of human FGR fetuses. IGFBP-1 was also hyperphosphorylated at Ser101, Ser119, and Ser169 in the liver of growth–restricted baboon fetus. mTOR signaling was markedly inhibited, whereas expression and activity of CK2 was increased in growth–restricted baboon fetal liver in vivo. Using HepG2 cells and primary fetal baboon hepatocytes, we established a mechanistic link between mTOR inhibition, CK2 activation, IGFBP-1 hyperphosphorylation, and decreased IGF-I–induced IGF-I receptor autophosphorylation. We provide clear evidence for IGFBP-1 hyperphosphorylation in FGR and identified an mTOR and CK2-mediated mechanism for regulation of IGF-I bioavailability. Our findings are consistent with the model that inhibition of mTOR in the fetal liver, resulting in increased CK2 activity and IGFBP-1 hyperphosphorylation, constitutes a novel mechanistic link between nutrient deprivation and restricted fetal growth.

Download Full-text

Influence of Cerebral Vasodilation on Blood Reelin Levels in Growth Restricted Fetuses

Diagnostics ◽

10.3390/diagnostics11061036 ◽

2021 ◽

Vol 11 (6) ◽

pp. 1036

Author(s):

Jara Pascual-Mancho ◽

Pilar Pintado-Recarte ◽

Carlos Romero-Román ◽

Jorge C. Morales-Camino ◽

Concepción Hernández-Martin ◽

...

Keyword(s):

Fetal Growth ◽

Fetal Growth Restriction ◽

Molecular Mechanisms ◽

Umbilical Artery ◽

Normal Weight ◽

Growth Restriction ◽

Future Research ◽

Weight Group ◽

Normal Weight Group ◽

Umbilical Artery Doppler

Fetal growth restriction (FGR) is one of the most important obstetric pathologies. It is frequently caused by placental insufficiency. Previous studies have shown a relationship between FGR and impaired new-born neurodevelopment, although the molecular mechanisms involved in this association have not yet been completely clarified. Reelin is an extracellular matrix glycoprotein involved in development of neocortex, hippocampus, cerebellum and spinal cord. Reelin has been demonstrated to play a key role in regulating perinatal neurodevelopment and to contribute to the emergence and development of various psychiatric pathologies, and its levels are highly influenced by pathological conditions of hypoxia. The purpose of this article is to study whether reelin levels in new-borns vary as a function of severity of fetal growth restriction by gestational age and sex. We sub-grouped fetuses in: normal weight group (Group 1, n = 17), FGR group with normal umbilical artery Doppler and cerebral redistribution at middle cerebral artery Doppler (Group 2, n = 9), and FGR with abnormal umbilical artery Doppler (Group 3, n = 8). Our results show a significant association of elevated Reelin levels in FGR fetuses with cerebral blood redistribution compared to the normal weight group and the FGR with abnormal umbilical artery group. Future research should focus on further expanding the knowledge of the relationship of reelin and its regulated products with neurodevelopment impairment in new-borns with FGR and should include larger and more homogeneous samples and the combined use of different in vivo techniques in neonates with impaired growth during their different adaptive phases.

Download Full-text

Impact of risk factors for Fetal Growth Restriction (FGR) on intrauterine growth and birthweight

Endocrine Abstracts ◽

10.1530/endoabs.51.oc4.8 ◽

2017 ◽

Author(s):

Reena Perchard ◽

Lucy Higgins ◽

Edward Johnstone ◽

Peter Clayton

Keyword(s):

Risk Factors ◽

Fetal Growth ◽

Fetal Growth Restriction ◽

Growth Restriction ◽

Intrauterine Growth

Download Full-text

FETAL GROWTH RESTRICTION WITH EARLY AND LATE MANIFESTATION, PROGNOSTIC MARKERS

Global problems of modernity ◽

10.26787/nydha-2713-2048-2020-1-10-11-12-27-30 ◽

2020 ◽

pp. 27-30

Author(s):

Yakubova D.I.

Keyword(s):

Risk Factors ◽

Pregnant Women ◽

Fetal Growth ◽

Fetal Growth Restriction ◽

Prenatal Screening ◽

Prognostic Markers ◽

Growth Restriction ◽

Late Manifestation ◽

Late Form ◽

Early Manifestation

Objective of the study: Comprehensive assessment of risk factors, the implementation of which leads to FGR with early and late manifestation. To evaluate the results of the first prenatal screening: PAPP-A, B-hCG, made at 11-13 weeks. Materials and Methods: A retrospective study included 110 pregnant women. There were 48 pregnant women with early manifestation of fetal growth restriction, 62 pregnant women with late manifestation among them. Results of the study: The risk factors for the formation of the FGR are established. Statistically significant differences in the indicators between groups were not established in the analyses of structures of extragenital pathology. According to I prenatal screening, there were no statistical differences in levels (PAPP-A, b-hCG) in the early and late form of FGR.

Download Full-text