Gene expression of insulin-like growth factors (IGFs), the type 1 IGF receptor, and IGF-binding proteins in dexamethasone-induced fetal growth retardation

Abstract

Altered gene expression and/or actions of the insulin-like growth factors (IGFs) have been implicated in the mediation of both pre- and postnatal growth retardation secondary to glucocorticoid excess. To investigate this possibility, we assessed the gene expression of the IGFs, the type I IGF receptor, and IGF-binding proteins (IGFBPs) in 20-day gestation liver and lung of growth-retarded fetuses whose mothers were treated with dexamethasone (DXM; 100 micrograms, ip, daily) on gestation days 15-19 (gestation = 21-22 days). DXM treatment in dams produced fetal growth retardation without decreasing litter size (32% decrease in fetal body weight). Both fetal liver and lung demonstrated decreased wet weight (48% and 47%, respectively) and DNA content (65% and 51%, respectively) compared to control animals. Our results suggest that increased expression of IGFBP-1, and possibly IGFBP-2, is involved in mediating the marked growth retardation. As assessed by solution hybridization assays and Northern blot analysis, there was an 8.5-fold increase in IGFBP-1 mRNA expression in the livers of DXM-treated fetal animals compared to that in sham-injected controls (P less than 0.002). IGFBP-2 mRNA expression was also increased (60%) in fetal liver, whereas IGFBP-3 was decreased (57%). In fetal lung, IGFBP-1 transcript abundance was also higher in DXM-treated fetal animals. Serum concentrations of IGFBP-1, but not those of IGFBP-2, were increased (approximately 4-fold) in the DXM-treated fetuses, as quantified by [125I]IGF-I ligand blotting and IGFBP-2 immunoblotting. Because hypoinsulinemia increases the expression of IGFBP-1 and -2, serum insulin concentrations were measured and found to be decreased in the DXM-treated fetuses (24 microU/ml) compared to control values (72 microU/ml). Analysis of mRNA expression for IGF-I, IGF-II, and the type 1 receptor transcripts did not support a role for decreased IGF or IGF receptor expression in the etiology of DXM-mediated growth retardation. IGF-I was unchanged in both liver and lung, and IGF-II transcripts were increased by 31% in liver and unchanged in lung of DXM-treated fetal animals. Northern analysis of hepatic and lung poly(A) RNA demonstrated no evidence for independent regulation of specific-sized IGF transcripts. Further, type 1 IGF receptor RNA abundance increased 42% in fetal liver and was unchanged in lung. Because IGFBPs may modulate IGF action, these results suggest that increased IGFBP-1, and possibly IGFBP-2, expression may be of importance in the etiology of DXM-induced fetal growth retardation.

Amniotic IGF-I supplementation of growth-restricted fetal sheep alters IGF-I and IGF receptor type 1 mRNA and protein levels in placental and fetal tissues

“…Exogenous glucocorticoids have been reported to reduce both circulating IGF-I concentrations and tissue IGF-I mRNA levels (Luo & Murphy 1989, Jensen et al 2002. However, other studies have reported no effect of glucocorticoids on circulating IGF-I concentrations or tissue IGF-I mRNA levels, but an increase in IGFBP expression, suggesting that IGF bioavailability may be decreased (Mosier et al 1987, Price et al 1992.…”

“…Several studies of growth restriction induced by different means in different species have reported a 1·7-to 10-fold upregulation of hepatic IGFBP-1 and/or BP-2 expression; for example, prolonged hypoxia in sheep (McLellan et al 1992), maternal fasting (Straus et al 1991), dexamethasone treatment (Price et al 1992) and being small for gestational age in the rat (Unterman et al 1990) and uterine artery ligation in the guinea pig (Carter et al 2005). We found a 1·7-fold increase in IGFBP-1 expression in liver in the saline-treated fetuses but this was not statistically significant.…”

Repeated maternal glucocorticoid administration and the developing liver in fetal sheep

“…Glucose intolerance in adult rats exposed to maternal dexamethasone in utero has been associated with elevations in hepatic glucocorticoid receptors (GR) and glucocorticoid-sensitive enzymes involved in gluconeogenesis such as phosphoenol-pyruvate carboxykinase (PEPCK) mRNA levels (Nyirenda et al 1998, Saegusa et al 1999. In rats, administration of maternal carbenoxolone, an inhibitor of a placental 11 -hydroxysteroid dehydrogenase (11 HSD) thus permitting increased passage of maternal glucocorticoids to the fetus (Whorwood et al 1993), has been shown to reduce birth weight in a manner similar to that observed with dexamethasone treatment (Price et al 1992, Levitt et al 1996, Nyirenda et al 1998. Moreover, adult male offspring demonstrated altered glucose tolerance indicated by higher fasting glucose levels and elevated glucose and insulin responses to a glucose challenge.…”

IGF and IGF-binding protein expression in the growth plate of normal, dexamethasone-treated and human IGF-II transgenic mice

“…In experimental animal models, high doses of GCs also have a growthsuppressive effect on longitudinal bone growth (Price et al 1992, Leili & Scanes 1998, Rooman et al 1999, Silvestrini et al 2000. GCs have been shown to act locally to inhibit longitudinal growth, suggesting a local mechanism within the growth plate (Baron et al 1992, Silvestrini et al 2000.…”

“…In addition, GCs regulate the expression of IGFs (Jux et al 1998) and IGFBPs (Koedam et al 2000) in chondrocytes in vitro. Few data are available, however, concerning the regulation by GCs in vivo (Price et al 1992) and it has been reported that serum levels of IGF axis components provide little insight into the mechanisms of GC-induced growth retardation and the possible involvement of the IGF axis components therein (Ward et al 1999). Therefore, in order to elucidate the possible involvement of IGF axis components in GC-induced growth retardation, it is important to study locally produced IGFs and IGFBPs and their regulation by GCs in the growth plate.…”