Zhang XQ. Intrauterine growth restriction and genetic determinants - existing findings, problems, and further direction. World J Obstet Gynecol 2012; 1(3): 20-28 [DOI: 10.5317/wjog.v1.i3.20]
Corresponding Author of This Article
Xiu-Quan Zhang, MD, PhD, Department of Obstetrics and Gynecology, Department of Surgery, Division of Cardiothoracic Surgery, University of Utah School of Medicine, Salt Lake City, UT 84124, United States. xiuquan.zhang@hsc.utah.edu
Article-Type of This Article
Review
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Xiu-Quan Zhang, Department of Obstetrics and Gynecology, Department of Surgery, Division of Cardiothoracic Surgery, University of Utah School of Medicine, Salt Lake City, UT 84124, United States
ORCID number: $[AuthorORCIDs]
Author contributions: Zhang XQ solely contributed to this paper.
Correspondence to: Xiu-Quan Zhang, MD, PhD, Department of Obstetrics and Gynecology, Department of Surgery, Division of Cardiothoracic Surgery, University of Utah School of Medicine, Salt Lake City, UT 84124, United States. xiuquan.zhang@hsc.utah.edu
Telephone: +1-801-5815311 Fax: +1-801-5853936
Received: April 18, 2012 Revised: July 6, 2012 Accepted: September 12, 2012 Published online: October 10, 2012
Abstract
Fetal growth is determined largely by the nutrient supply, placental transport function, and growth hormones. Recently, gene mutation and expression, especially of those genes associated with the proteins that are related to the fetal growth, have been reported to play an important role in the development of intrauterine growth restriction (IUGR). Fetal growth epigenetics, a new concept in fetal growth, has resulted from studies on fetal programing. This paper outlines the findings of our serial studies on IUGR, and summarizes data on IUGR animal models, placental function in transferring nutrients, cell proliferation dynamics in IUGR, and experimental treatment of IUGR. We review genetic approaches to IUGR, especially those relating to growth factor genes, angiotensinogen genes and other gene mutations. We also discuss the epigenetics of fetal growth and future study directions on fetal growth restriction. These should be valuable in elucidating the mechanisms employed by the fetus and in helping to develop interventional strategies that might prevent the development of IUGR.
Intrauterine growth restriction (IUGR) is an important obstetric complication affecting 5% of pregnancies[1]. This condition represents an in utero shift from the expected pattern of fetal growth potential into reduced birth weight. This leads to increased risk for intrauterine compromise, stillbirth, preterm birth and adverse perinatal and long-term outcomes[2-5]. It is generally accepted that IUGR is associated with a poor nutrient and oxygen supply, although the specific mechanisms involved in IUGR development are mostly unknown.
Fetal growth is determined largely by the nutrient supply, which is dependent on placental transport functions. Though placental transportation depends on the concentration gradient between maternal and fetal blood, it seems that placental blood flow and the activity of specific membrane transporters play more important role[6,7]. Regardless of what the exact mechanism for IUGR might be, growth factors and their interaction with their receptors are most likely to be involved[8]. In addition to nutrition, placental function, and growth hormones, gene mutation and expression have been reported to be associated with IUGR[9-13]. Those genes associated with the proteins that are related to the fetal growth such as growth factor genes are particularly implicated. In recent years, a new concept in fetal growth, fetal growth epigenetics, has resulted from studies on fetal programing[3,14-16].
The information in this paper outlines findings from our serial studies on IUGR and reviews the genetic approaches in recent years. This should be valuable in the elucidation of the mechanisms employed by the fetus and help in the development of interventional strategies that might prevent the development of IUGR.
EXISTING FINDINGS
IUGR animal models
Several methods have been used to establish the animal model of IUGR. These include uterine artery ligation, passive smoking, alcohol exposure, administration of L-arginine or actinomycin, and maternal malnutrition. To date, mouse, rat, guinea pig, rabbit, sheep, monkey, dog, and pig have been used to establish the IUGR model[17-19].
We have reported the establishment of an IUGR rabbit model using passive smoking and have studied the fetal and maternal plasma amino acid concentration, the blood flow of utero-placenta and changes in cell proliferation cycle in brain, liver and placenta[20,21]. In addition, the effect of treatment with histiocyte activators and vasodilators on the IUGR was also observed[7,18]. Recent studies on gene mutations have shown that specific genes might play an important role in the development of IUGR[9-16].
Active transfer of nutrients through the placenta
Although fetal plasma nutrient concentration is related to the maternal concentration, some amino acids, especially most essential amino acids, show higher concentrations in fetal plasma than in maternal plasma, proving that the absorption of amino acids from the maternal body to the fetus is an active process[22]. Maternal rabbit total plasma amino acid concentration at 28-d of pregnancy was less than that of non-pregnant rabbits. These changes were more apparent with essential amino acids. In the rabbit IUGR model, smoking could reduce the ability of the placenta to transfer nutrients from the maternal to the fetal side. It was found that the total amino acid concentration in fetus was lower in rabbits with IUGR induced by smoking than in controls. In fetal plasma, the levels of all essential amino acids, except threonine, and of nonessential amino acids including serine, glutamine, alanine, tyrosine, arginine and histidine showed the same patterns in smoking groups as in the control group[7,20].
Dynamics of cell proliferation in IUGR
Cell proliferation in the fetus is very active, especially in early embryo phase. Proliferation depends on the cell division, as measured by analyzing the cell cycle using flow cytometry. The more rapid the cell division, the shorter the G0 and G1 phases. In another words, lower proliferation will leave more cells in G0 or G1 phase, while active proliferation will result in more in S + G2 + M phases. By analyzing the cell cycle using flow cytometry, we found that the ratio of the cells in G0 + G1 phases to the total cells was increased and the ratio of the cells in S + G2 + M phases to the total cells was decreased in fetal brain, liver and placenta in IUGR rabbits induced by passive smoking. This change was particularly prominent in brain. These results suggest that the proliferation of the fetal cells and placenta were inhibited significantly, resulting in growth retardation of the fetus. This data demonstrated that the transformation from G1 to S phases was restricted in IUGR and that cell proliferation is prevented[21,23].
Experimental treatment of IUGR
IUGR rabbits caused by passive smoking were treated with histiocyte activators (include ATP, Co-A, and Cyt-C) and vasodilators (InjectioSalviaeMoltiorrhizaeComposita). The results showed that the vasodilators could increase the uteroplacental blood flow by about 35% and induced some progress in fetal development, as indicated by a 9.8% increase in fetal body weight. The fetal plasma amino acid concentration was also higher than that of the control group. It seems that the histiocyte activators were more effective in promoting fetal development (24.6% increase of fetal body weight) than the vasodilators. Although the effect of the histiocyte activators was not as marked as that of vasodilators in increasing uteroplacental blood flow, the amino acid concentration of fetal plasma increased more after histiocyte activator treatment than vasodilator treatment. This suggests that vasodilators could be used to treat the IUGR caused by vasospasm. Histiocyte activators appear to be better than vasodilators in increasing the nutrient transportation of the placenta[24].
IUGR AND GENE APPROACHES
Although the human genome contains about 30 000 genes only a small number of them are turned on within a particular tissue type. Cell proliferation and differentiation results from the ability of tissues to express different genes from the same basic set of genetic information stored in DNA. This small subset of genes allows the cells to produce proteins unique to their functions. Although gene expression is controlled by epigenetic modifications, the gene sequence obviously plays the most important role in the proliferation and differentiation of cells.
IUGR and growth factor genes
Several studies have demonstrated altered concentrations of human placental growth hormones (hPGH), insulin-like growth factor-I (IGF-I) and IGF banding protein (IGFBPs) in the maternal circulation and the fetal compartment in pregnancies with IUGR[25,26]. Koutsaki, evaluating the expression status of the hPGH, the IGF-I, IGFBP-1 and IGFBP-3 genes in placentas from human IUGR pregnancies of no apparent etiology, found that hPGH, IGF-I, IGFBP-1 and IGFBP-3 expression was significantly lower than that in placentas showing normal fetal growth. However, these alterations are not known causative factors of IUGR or associated with other pathogenetic mechanisms[27].
Type I insulin-like growth factor receptor (IGF-IR) is widely expressed across many cell types in fetal and postnatal tissues. The activation of this receptor, after the binding of secreted IGF-I and IGF-IR promotes cell differentiation and proliferation. An association has been found between IGF-IR gene mutations and low birth weight[28]. IGF-IR gene anomalies such as heterozygous IGF-IR mutation or insufficiency of the IGF-IR gene were found in patients presenting with low birth weight and birth height[29,30]. This phenotype is associated with family history of low birth weight and a normal or increased IGF-I level and/or a normal or increased GH response to GH stimulation test[31,32]. However, such patients show less response to GH treatment than common small for gestational age short-stature patients[33].
Choi et al[34] reported a family with both a novel heterozygous mutation of the IGF-1R gene and a segmental deletion encompassing the entire IGF-1R, resulting in IGF-I resistance and leading to IUGR and postnatal growth failure. In vitro studies of fibroblasts from subjects carrying the gene clearly demonstrated reduced IGF-1R expression and subsequent IGF-I resistance, as assessed by IGF-1R phosphorylation and post-receptor signal transduction. This indicates that IGF-1R mutations should be considered in the differential diagnosis of familial IUGR patients with persistent short stature[34]. Umbers found that material inflammation of the placenta could disturb the IGF expression and cause IUGR[35].
Experiments in animals demonstrated the importance of IGF in the regulation of both intrauterine and postnatal growth. Baker reported that isolated inactivation of IGF-I resulted in restrictions in fetal development (40% delay compared with wild type mice) and Liu found that postnatal growth was further impaired, reaching only 30% of that in normal mice[36,37]. Knockout of both IGF-I and IGF-II or knockout of both IGF-II and IGF-I receptors resulted in severe growth retardation (Figure 1)[38]. These experiments clearly demonstrated that IGF-I is a major regulator of both pre- and postnatal growth. Several authors reporting IGF-IR gene mutations observed effects on birth weight, height, serum IGF-I and additional complications (Table 1).
Figure 1 Effects of disruption of the insulin-like growth factor system on fetal growth in mice, expressed as a percentage of normal body weight[38].
IGF: Insulin-like growth factor.
IUGR and angiotensinogen gene
IUGR has been associated with insufficient placental circulation, which may result from failed maternal physiologic changes such as abnormal spiral artery remodeling and reduced maternal blood volume. Morgan reported that spiral artery remodeling might be related to the angiotensinogen gene[39]. We compared maternal blood DNA in 174 patients with IUGR, 62 patients with placental abruption, and 60 patients with both preeclampsia compared with a control group comprising 400 consecutive cases of women with term pregnancies and infants with birth weight between the 5th and 95th percentiles. We also examined 162 DNA samples from fetal blood with IUGR and 240 normal fetuses from control group for the Thr235 polymorphism[40] (Tables 2 and 3).
Figure 2 Real-time polymerase chain reaction for angiotensinogen M235T genotyping with a single labeled fluorescein probe[42].
A: 5’-fluorescein-labeled 23-mer (blocked at the 3’-end with phosphate) homologous to the wild-type sequence, covered the polymorphic site with the fluorescein opposite two genes; B: The probe was included in the PCR amplification mixture with primers. Melting curve data are presented as fluorescein vs temperature; C: Curves for homozygous wild type (peak at 69.4oC), homozygous mutant type (peak at 63.54oC), heterozygous (two peaks at 63.54oC and 69.44oC respectively) and no-template control are shown; D: Placental cross section HE staining from AGT MM, MT, and TT placentas. Quantitative analysis of the placenta indicated that the villus area (red) and capillary area (bright red) in smoking-induced intrauterine growth restriction were significantly decreased.
According to the AGT genotyping results using real time PCR, angiotensinogen genotypes were divided into three groups: MM (homozygous for angiotensinogen Met235 allele), TT (homozygous for angiotensinogen Thr235 allele), and MT (heterozygous). It has been demonstrated that maternal and fetal angiotensinogen Thr235 genotypes are associated with an increased risk of IUGR[40]. The angiotensinogen Thr235 allele may predispose women to deliver growth-restricted fetuses. Further studies have shown that mutation of angiotensinogen gene Thr235 is also a risk factor for preeclampsia and placental abruption[41] (Table 2). In addition, quantitative analysis of the placenta indicated that the villus area was decreased significantly in the IUGR group induced by smoking exposure. The capillary area in the villus was also significantly less in IUGR groups. There were also some important changes observed under the electronic microscope, such as the retardation and reduced number of microvilli, fatty degeneration and mitochondrial swelling of the syncytial cells[42]. Studies on human placenta showed that villus volume and capillary area in IUGR were significantly decreased (Figure 2 and Table 4).
It has been reported in many publications that certain gene mutations are associated with IUGR (Table 3). Pericentric inversion of chromosome 6 causes haplo-insufficiency of the CDK19 gene resulting in microcephaly, congenital bilateral falciform retinal folds, nystagmus, and mental retardation[9]. Chromosome 1p32-p31-deletion syndrome and haplo-insufficiency of the NFIA gene may present as ventriculomegaly, corpus callosum hypogenesis, abnormal external genitalia, and IUGR in the third trimester[10]. Smigiel reported on two brothers affected with restrictive dermopathy, who died in the neonatal period[43]. Molecular analyses were performed in the second child, for whom biological material was available, and on both parents. Compound heterozygous frameshifting mutations were identified in exon 1 (c.50delA) and exon 5 (c.584_585delAT) of the ZMPSTE24 gene. The autosomal recessive inheritance was confirmed by genomic analysis of the parents. Partial loss of Ascl2 function affects all three layers of the mature placenta and causes IUGR[44]. The expression of c-fos is critical in the oxidative stress pathway. In fetal alcohol syndrome in mouse, it was shown that alcohol administration during pregnancy results in differential gene expression in the stress signal pathway, particularly in c-fos. C-fos expression in the decidua increases from 6 to 24 h after alcohol injection, but does not change in the embryo, which may contribute to alcohol-induced damage in fetal alcohol syndrome (Table 5)[45].
Severe growth retardation, absence of spongiotrophoblast layer, embryonic lethality[61]
PEG3
Inhibits WNT-signalling
Placental and fetal growth restriction and abnormal maternal behavior[62]
PLAGL1 Zac1
Tumor suppressor
Skeletal defects, neonatal lethality, IUGR, and disrupted transactivation of Igf2[63]
SFRP2
WNT signaling
Reduction in vitro of extra villous trophoblast invasion[64]
HBII-85/PWScr
C/D Box small RNA
Implicated in Prader Willi, Postnatal growth retardation[65]
Epigenetics of fetal growth
Mechanisms leading to the attenuation of fetal birth weight and adverse pregnancy outcomes are complex. Many studies have begun to focus, not only on the contribution of maternal and fetal genes to phenotypic outcome, but also on epigenetic changes associated with fetal growth[46].
Imprinted genes have a central role in the development and function of the placenta and have been implicated in a variety of disorders affecting fetal growth[14-16,47,48]. Gene inactivation studies in mice and chromosomal rearrangements in humans have demonstrated that many of these imprinted genes play key roles in placental development and function as well as in fetal growth. Those studies have also demonstrated that imprinted genes act in a complex manner at many levels to affect the energy balance between the mother and fetus. More recent studies also support a role of imprinted genes in a compensatory response to reduced fetal growth in humans.
During early embryonic development, the first stage of embryo differentiation establishes two cell lineages. These are the inner cell mass that forms all the tissues of the adult, and the trophectoderm that eventually produces placental structures. Generally speaking, the inner cell mass becomes gene hypermethylated and the trophectoderm becomes gene hypomethylated. These methylation patterns may be preserved throughout the whole pregnancy period[49,50]. Mouse and human models suggest the epigenetic regulation of fetal growth may also play a significant role through the placental imprinted genes.
Lambertini et al[48] investigated the differential methylation status of the imprinted genome to gain insights into the importance of the epigenetic regulation of these genes in fetal development by comparing IUGR with normal placentas. They found that differential methylation showed a highly significant correlation with gene length. The data also suggests that differential methylation changes in growth-restricted placentas occur throughout the genomic regions encompassing genes actively expressed in the placenta. Kumar studied 11 IGF related genes and found upregulated ZNF127 gene expression and down regulated PHLDA2 gene expression. This change confirmed an increased placental expression of growth-promoting imprinted genes and decreased expression of growth-suppressive imprinted genes with advancing gestational age. These changes in placental gene expression could potentially explain accelerated fetal growth seen in the third trimester[51]. McMinn presented an excellent example of the complexity of the imprint gene in placenta[52]. He showed that a small group of imprinted genes (PHLDA2, MEST, MEG3, GATM, GNAS and PLAGL1) and an additional 400 genes were affected in IUGR placentas.
Many studies have reported changes in imprinted gene expression and methylation levels in response to IUGR. These include reports of abnormal methylation in multiple imprinted loci[16], IUGR placental methylation decrease in the IGF2/H19 locus[53], and differential expression in multiple imprinted genes in IUGR placentas[54].
PROBLEMS AND FUTURE DIRECTION
IUGR animal models and clinical IUGR
IUGR animal models have been established by several methods. Most of the methods affect nutrients, placental function, or maternal fetal circulation although some may affect gene expression. These IUGR models have provided valuable simulations allowing study human IUGR, especially the IUGR resulting from nutritional factors, placental function, or toxic materials. However, no animal IUGR model induced by gene mutation or altered gene expression, simulating human IUGR related to specific genes has been reported. To date, the development of gene engineering and transgenic techniques have made it possible to produce specific gene mutation/expression altered IUGR animal models. This kind of animal model will provide a direct and definite method to study the specific genes involved in IUGR.
Single gene study and many genes related to IUGR
A concern of the present studies is that only limited numbers of genes have been studied among the thousands genes that are expressed in placenta, while many genes are in fact associated with fetal growth. Evaluation of their important roles in fetal growth still requires the accumulation of multiple collections of data on the mutation, phenotype, epigenetics, and metabolomics associated with fetal growth characteristics. Specifically, the pathways involved in the mutation or epigenetics resulting in IUGR phenotype are mostly unknown. Basic study of the pathways involving these genes may help us to understand why and how the phenomenon occurs at the molecular level.
Role of genes in IUGR
Although it seems simple to define the diagnosis of IUGR as an estimated fetal weight falling below the 10th percentile of normal body weight, that definition also captures births that are part of the normal variation in a population. Clinical diagnostic criteria are based on the fetal growth curve and umbilical blood velocity abnormalities. However, IUGR is still an extremely complex phenotype to dissect because of the many factors involved, maternal, fetal, placental, and environmental. Almost all recent gene expression studies are based on small number of samples. It is unrealistic to expect to find one or a few genes responsible for causing IUGR using this approach. Most gene expression studies have found genes that are dysregulated in IUGR. In addition, most of these genes, such as IGF-I, IGFBP1, corticotropin-releasing hormone, are reported to be related to the regulation of cell division and proliferation. We are still unable to to determine whether this is a compensatory response to restricted fetal restricted growth or a the factors which induces fetal growth restriction. The use of transgenic engineering technique in animals to study some specific gene may provide an ideal model to study the phenotype related to these genes in human clinical subjects.
Gene promoting and IUGR
Some specific imprinted genes are related to IUGR. These genes can be separated into two categories: genes participating in reducing fetal growth, and those which increase fetal growth as a compensatory response when it is sensed that the fetus is at risk. The evidence supporting mutations in imprinted genes that negatively influence fetal growth is summarized in the table and genes which the positively influence fetal growth are also indicated. We may expect that reducing expression of the negative genes and increase the expression of the positive genes would result in fetal growth. However, there is still a long way to go from basic animal model studies to reach clinical applications using gene-regulating techniques.
Footnotes
Peer reviewer: Chie-Pein Chen, MD, PhD, Division of High Risk Pregnancy, Mackay Memorial Hospital, 92, Sec. 2 Zhong-Shan North Road, Taipei 104, Taiwan
S- Editor Wang JL L- Editor Hughes D E- Editor Zheng XM
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