Altered Placental and Fetal Expression of IGFs and IGF-Binding Proteins Associated With Intrauterine Growth Restriction in Fetal Sheep During Early and Mid-Pregnancy

Abstract

ABSTRACT:The insulin-like growth factors (IGFs) are postulated to be altered in association with the development of intrauterine growth restriction (IUGR). The present studies examined placental and fetal hepatic mRNA concentration of components of the IGF system at two time points (55 and 90 d gestational age, dGA; Term 147 dGA) in a hyperthermia (HT)-induced sheep model of placental insufficiency-IUGR. Maternal plasma insulin and IGF-I were constant at 55 and 90 dGA and were unaffected by treatment. Umbilical vein insulin concentrations tended to be reduced at 90 dGA following HT exposure. Caruncle IGF-I mRNA was increased at 90 dGA in HT placentae (p Ͻ 0.05), while cotyledon concentrations were constant over gestation and unaltered by treatment. In control cotyledons, IGF-II mRNA concentration increased (p Ͻ 0.01) and IGFBP-3 decreased between 55 and 90 dGA (p Ͻ 0.01). Cotyledon IGF-II and caruncle IGFBP-4 mRNA were elevated at 55 dGA in HT placentae compared with control (p Ͻ 0.01 and p Ͻ 0.05 respectively). Fetal hepatic IGF-I, IGFBP-2, -3 and -4 concentrations rose over gestation (p Ͻ 0.05), but there were no treatment effects. These data suggest that changes in placental IGF expression in early and mid gestation may predispose the pregnancy to placental insufficiency, resulting in inadequate substrate supply to the developing fetus later in gestation.

Effects of early gestation GH administration on placental and fetal development in sheep

“…In the caruncle, IGFBP-2 was unaffected by maternal GH treatment. Previously, it was believed that IGFBP-1 was not expressed beyond 21 dGA (Wathes et al 1998, de Vrijer et al 2006; however, here we could detect changes in IGFBP-1 by treatment at 55 dGA. We do not discount the previous results, as our detection of IGFBP-1 is most likely due to the increased sensitivity of qPCR versus hybridization technologies in detecting transcripts.…”

“…5 8C to 95 8C. For the qPCR analysis, cDNA for ovine IGF-I, IGF-II, and IGFbinding proteins (BP) 1, 2, 3, and 4 (de Vrijer et al 2006) and RPS15 (Rozance et al 2007) were used as standard templates. The standard curve template concentrations spanned 100 to 1!10 K5 pg/ml at tenfold increments.…”

The IGF Axis and Placental Function

“…Many studies have reported increased placental expression of IGF-I and IGF-II in IUGR pregnancies [33, 34] and, similarly, elevated levels of placental IGF-I and-II mRNA have been observed in a sheep model of IUGR [35]. These findings are somewhat surprising as, like in cord blood, a decrease in placental IGF levels might have been anticipated.…”

The impact of ovarian stimulation for IVF on the developing embryo

“…Elevated expression levels of paternally imprinted gene IGF2 in the placenta have been correlated with foetal growth restriction in humans (Street et al 2006) and sheep (de Vrijer et al 2006) and with early embryonic lethality of somatic cell nuclear transferderived cows (Oishi et al 2006). Since low birthweight in humans may be an important risk factor for the development of neurological disorders and adult-onset diseases such as coronary heart disease, stroke, hypertension, type II diabetes and osteoporosis, ovarian stimulation could even have adverse effects in adult life (Fleming et al 2004).…”