Insulin-like growth factor-binding protein-1 (IGFBP-1) mediates hypoxia-induced embryonic growth and developmental retardation

Abstract

Although reduced fetal growth in response to hypoxia has been appreciated for decades, we have a poor understanding of the effects of hypoxia on embryonic development and the underlying cellular and molecular mechanisms. Here we show that hypoxia treatment not only resulted in embryonic growth retardation but also caused significant delay in developmental zebrafish ͉ heart development ͉ craniofacial skeleton ͉ morphogenesis ͉ oxygen H ypoxic stress causes major metabolic changes in all organisms requiring oxygen. Hypoxic stress also influences fetal growth and development and the pathogenesis of several human diseases, including intrauterine growth restriction (IUGR) (1-3). Reduced birth weight is also observed at high altitudes (4). IUGR not only increases fetal and neonatal morbidity and mortality, but also increases the risk of having adult diseases, such as cardiovascular disease, type-2 diabetes, obesity, and hypertension (5).Recent evidence suggests that hypoxia may influence fetal growth through its connection to the insulin-like growth factor (IGF) signaling system. IGFs are well known fetal growth factors (6-9). Several groups have reported that the circulating level of IGF-binding protein (IGFBP)-1, a secreted protein that binds to IGF in extracellular environments, is elevated in IUGR fetuses (10-12) and that there is a striking inverse correlation between IGFBP-1 levels and fetal size (13). In addition, higher maternal serum IGFBP-1 levels are found at higher altitude (14). In vitro studies with cultured human cells and in vivo studies with mammalian animal models suggest that IGFBP-1 gene expression is elevated in hypoxic conditions (15)(16)(17) and that this up-regulation is mediated through the hypoxia-inducible factor (HIF)-1 pathway (16). Because IGFBP-1 binds IGFs with high affinity and inhibits IGF activities on cell growth in vitro (18,19) and because IGFBP-1-overexpressing transgenic mice had reduced birth weight (20-22), it was postulated that the elevated IGFBP-1 plays a major role in hypoxia-caused IUGR by binding fetal IGFs and inhibiting their growth-promoting activities (3,16,17). This appealing model, however, has not been directly tested in vivo, and a causative relationship between the elevated IGFBP-1 expression and IUGR has not been established. Moreover, the impact of hypoxia on early developmental processes, such as morphogenesis, is poorly understood, and the role of IGFBP-1, if any, in mediating the hypoxic effects on embryonic development is unknown.The zebrafish has now become an informative vertebrate model organism for the study of IGF signaling in early development (23). Zebrafish embryos develop externally, eliminating the complication of maternal compensation. Fast developing and transparent zebrafish embryos make it possible to manipulate environmental factors and observe the phenotypic changes in organ formation in real time. Furthermore, major components of the zebrafish IGFsignaling pathway, including IGF ligands, receptors, IGFBPs, and intracellular signal transdu...

Changes in interleukin-6 and IGF system and their relationships in placenta and cord blood in newborns with fetal growth restriction compared with controls

“…It is still unknown which mechanisms in the human fetus increase total and Np-IGFBP-1, although some have been suggested (37)(38)(39). IGFBP-1 concentrations in cord serum may be increased in FGR (10), as we confirmed.…”

Toxicogenomic Responses of Zebrafish Embryos/Larvae to Tris(1,3-dichloro-2-propyl) Phosphate (TDCPP) Reveal Possible Molecular Mechanisms of Developmental Toxicity

“…Igfbp1a is a secreted protein and can bind to insulin-like growth factors in extracellular environment with high affinity and thus inhibit their grow-promoting activity. 23,24 A previous study demonstrated that overexpression of igfbp1a caused growth and developmental retardation in zebrafish embryos. 24 Slc38a4 is an amino acid transporter and was suggested to be involved in the control of embryogenic growth in vertebrates by regulating the transport of amino acid.…”

“…23,24 A previous study demonstrated that overexpression of igfbp1a caused growth and developmental retardation in zebrafish embryos. 24 Slc38a4 is an amino acid transporter and was suggested to be involved in the control of embryogenic growth in vertebrates by regulating the transport of amino acid. 25−27 A previous study reported that the down-regulation of slc38a4 was positively associated with postnatal growth deceleration in mice.…”

Genetic disorders in the GH–IGF-I axis in mouse and man

“…Indeed, IGFBP-1 levels and mRNA expression are markedly elevated in the umbilical cord blood of babies with profound and prolonged hypoxia, which is considered a leading cause of IUGR (72). In a recent study, the key role of IGFBP-1 in mediating the effects of hypoxia on fetal growth was confirmed in zebrafish, suggesting this is a conserved physiological mechanism to restrict IGFstimulated growth under hypoxic conditions (73).…”