Androstenedione synergizes with stress or prenatal drug exposure to retard fetal growth: role of IGF.

Pregnant Sprague-Dawley dams were implanted with a Silastic capsule (3 or 10 mm) containing androstenedione (AN) or cholesterol prior to being administered one of several treatments that create an endocrine profile of stress: maternal exposure to alcohol, pair feeding (PF), cocaine (COC), or restraint stress (RS). Controls (chow fed, CF) were left undisturbed during pregnancy. Treatments were administered from day 14 to day 22 of gestation. Fetuses were delivered by cesarean section on day 22. Results revealed that administration of AN to pregnant dams at a dose that does not influence fetal growth by itself can retard fetal growth in the presence of alcohol, PF, COC or RS. Data indicate that these effects are not directly attributable to changes in adrenocorticotropin (ACTH) or corticosterone levels. Preliminary results suggest a role for insulinlike growth factor (IGF) binding proteins (IGFBPs). Overall, these data demonstrate that AN can synergize with drugs and/or stress to enhance intrauterine growth retardation (IUGR). One underlying cause of this synergism between stress-related environmental events and androgenic actions on fetal growth may be increased expression of IGFBPs, which can sequester IGFs, thereby inhibiting their trophic actions on fetal and/or placental tissue.

In utero exposure to ethanol alters mRNA for insulin-like growth factors and insulin-like growth factor-binding proteins in placenta and lung of fetal rats.

Insulin-like growth factors I and II (IGF-I and IGF-II) play a role in regulating fetal growth and development. Their actions in target tissues are modulated in part by binding to IGF binding proteins 1 and 2 (IGFBP-1 and IGFBP-2). In this study, we examined the effect of fetal exposure to alcohol IGF-I and on IGF-II and IGFBP-1 and IGFBP-2 mRNA in placenta and fetal lung tissue. Timed-pregnant Sprague-Dawley dams were fed a diet consisting of 35% ethanol-derived calories [alcohol-fed (AF)], an Isocaloric diet with sucrose substituted for alcohol (pair-fed; PF), or ad libitum rat chow (CF). Alcohol feeding began on gestational age (G) 14. At G20, dams were killed, and we examined placenta and fetal lung for the steady-state levels of mRNA for IGF-1 and IGF-II and for IGFBP-1 and IGFBP-2. In all dams, body weight increased throughout gestation, and there were no differences between the three groups. At G20, the mean weight for the fetuses from the AF group was lower (p < 0.001) than the fetuses from the CF and PF groups. Steady-state mRNA levels were detected in fetal lung and in placentas by Northern-blot hybridization analysis and semiquantitated by slot-blot hybridization analysis. Multiple transcripts for IGF-I and IGF-II, 1.8 kb species for IG-FBP-1 and 1.6 kb species for IGFBP-2 were detected from total RNA isolated from the fetal lung and placenta, Slot-blot hydridization analysis of fetal lung RNA showed that IGF-I mRNA was significantly increased (p < 0.001) in AF males and females by 4.0 +/- 0.28-fold and by 3.25 +/- 0.2-fold, respectively. IGF-II transcript levels were not affected. IGFBP-1 and IGFBP-2 were increased in AF males, whereas only IGFBP-2 was increased in AF females. In the placenta, there was a significant increase in IGFBP-1 and IGFBP-2 transcripts [(p < 0.001) 1.75 +/- 0.5-fold and 3 +/- 0.53-fold increase, respectively]. No differences between the groups in serum levels of IGFBP-1 or -2 were detected when measured by Western-blot analysis. The increased gene expression for IGFBPs within fetal lung and placenta may decrease bioavailability of locally synthesized, IGFs that may contribute to the fetal growth retardation observed in this model system.