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.

Glucocorticoid exposure in late gestation permanently programs rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult offspring.

“…Perhaps the congruence of rapid growth in late gestation with the expression of key glucocorticoid-regulated growth factors, such as the insulin-like growth factor (IGF) system, may be of importance. Indeed hepatic production of IGF binding protein-1 (IGFBP-1), which neutralizes the actions of IGF-1, is markedly induced in late gestation fetuses by high-dose maternal dexamethasone treatment (33), and has been advocated as causal in the growth retardation observed. Furthermore, transgenic mice overexpressing IGFBP-1 have low birth weight and adult hyperglycemia (34), perhaps suggesting one mechanism through which glucocorticoids link low birth weight and abnormal glucose metabolism.…”

Insulin-Like Growth Factor Binding Proteins: New Proteins, New Functions

“…The inverse has also been shown, namely conditions of hyperinsulinemia decrease IGFBP-1 levels, including the postprandial period, obesity, large for gestational age infants, insulinomas, and congenital hyperinsulinism with hypoglycemia [25, 29]. Glucocorticoids and glucagon stimulate IGFBP-1 production in synergism with low levels of insulin [28, 30, 31, 32, 33]. Some cytokines [tumor necrosis factor-α (TNF-α), interleukin, (IL-1)-1β, and IL-6] can also stimulate IGFBP-1 in vitro and in vivo [34].…”

Fetal rat lung epithelium has a functional growth hormone receptor coupled to tyrosine kinase activity and insulin-like growth factor binding protein-2 production

“…Of the many cells and tissues studied in the rat for their response to GH, only adipocyte precursor cells responded to GH with increased IGFBP-2 (Peter et al 1993) and tyrosine kinase stimulation (Winston & Bertics 1992). In previous studies insulin and glucocorticoids altered IGFBP-2 mRNA levels in rat tissues (Ooi et al 1990, Price et al 1992, but in the rat lung IGFBP-2 was unaffected by glucocorticoids (Price et al 1992). The stimulation of IGFBP-2 mRNA and protein by GH raises the possibility that GH regulates IGF activity in the epithelial environment through IGFBP-2 which has been observed on the epithelial lumen of the lung (Hill et al 1989).…”