Fetal programming of insulin-like growth factor (IGF)-I and IGF-binding protein-3: evidence for an altered response to undernutrition in late gestation following exposure to periconceptual undernutrition in the sheep

Abstract

It has been demonstrated in several animal models that undernutrition in utero has significant long lasting effects on subsequent fetal and postnatal development. To address the hypothesis that the insulin-like growth factors (IGFs) may mediate such effects, our study examined whether a period of periconceptual maternal undernutrition could have a lasting influence on the IGF axis in the fetal sheep. Ewes were either allowed to feed ad libitum or kept undernourished from day 60 prior to mating until day 30 after conception, and then both groups were allowed to feed ad libitum. These groups were further divided at day 105 of gestation, either being fed ad libitum or undernourished until day 115 of gestation. Fetal and maternal blood samples were obtained at both day 105 and 115 of gestation. We describe the development of a specific homologous RIA to measure ovine IGF-binding protein-3 (IGFBP-3) in fetal and maternal sheep plasma. Fetal plasma IGFBP-3 and IGF-I concentrations were significantly (P<0·05) reduced at day 115 of gestation after maternal undernutrition. The fetal plasma IGFBP-2 levels were unchanged. The degree of reduction in fetal plasma IGFBP-3 and IGF-I between day 105 and 115 of gestation as a response to acute maternal undernutrition was significantly greater (P<0·05) in fetuses of mothers receiving low periconceptual nutrition. The response of maternal plasma IGFBP-3 and IGF-I to undernutrition did not depend on the level of periconceptual nutrition. Western blot data indicate that changes in either maternal or fetal plasma IGFBP-3 concentrations were not the result of increased proteolytic activity. These results suggest that exposure to maternal periconceptual undernutrition reprograms IGFBP-3 and IGF-I regulation in the developing sheep fetus, altering its response to undernutrition in late gestation.

Influence of maternal undernutrition and overfeeding on cardiac ciliary neurotrophic factor receptor and ventricular size in fetal sheep

“…This change in plasma IGF-1 levels correlates well with the absolute fetal weights under nutrition restriction (29.9% reduction) and overfeeding (22.2% increase). Earlier studies have indicated that maternal undernutrition during periconceptual and gestational periods may lead to significant falls in fetal IGF and IGF binding protein-3 (IGFBP-3) levels in sheep (17,20). Nonetheless, our data favored a role of IGF-1 rather than IGF-1R or IGFBP3 in altered fetal heart weights in response to nutrition restriction and overfeeding.…”

The effect of maternal undernutrition on ovine fetal growth

“…The fall in fetal insulin in underfed fetuses may have mediated this change due to IGFBP-2 being inversely regulated by this factor (review: Kelley et al 1996). In contrast, fetal plasma IGFBP-3 levels tended to decrease in fetuses from underfed mothers (P<0·2) as previously reported in sheep (Lee et al 1997, Gallaher et al 1998. Earlier studies have reported reduced plasma IGFBP-3 and IGF-I levels and IGF-I mRNA expression in the muscle, lung and kidney of fetal sheep when placental growth was restricted (Kind et al 1995).…”

“…Reductions in ovine fetal plasma glucose, insulin and IGF-I have been reported earlier following periods of maternal dietary restriction (Bauer et al 1995, Gallaher et al 1998. Glucose provides the fetus with 30% of its daily carbon and energy requirements in the fed state (Fowden 2001), whilst fetal insulin promotes tissue accretion and cell proliferation in bone and soft tissue (Fowden 1989(Fowden , 1995.…”

Maternal backfat depth in gestating sows has a greater influence on offspring growth and carcass lean yield than maternal feed allocation during gestation

“…Nissen et al (2005) also observed no alteration in foetal serum IGF-1 concentrations or glucose concentrations, an indicator of nutrient supply, with different feed allocations in gestation. In contrast, studies in guinea pigs (Dwyer and Stickland, 1992) and sheep (Gallaher et al, 1998) reported decreased foetal IGF-1 concentrations when maternal feed intake during pregnancy was restricted. IGF-1 can induce nitric oxide production in endothelial cells.…”