Year: 1995
Type: dissertation
Abstract: Growth of the mammalian fetus is dependent on the fetal genome and its interaction with various modulating factors, primarily the placental supply of essential fetal substrates.The insulin-like growth factors (IGF-I, IGF-II) are implicated as potential mediators of the effects of external influences, such as placental substrate supply, on fetal growth.Restriction of placental size in sheep retards fetal growth by limiting the delivery of nutrients and oxygen to the fetus.Placental growth can be experimentally restricted by surgical removal of most endometrial caruncles, the placental attachment sites, from the uterus of the non-pregnant ewe.To investigate the role of the IGFs as mediators of the influence of placental substrate supply on growth in utero, the relationship between fetal growth, circulating IGF-I and -II proteins and the expression of the genes for IGF-I and -II in fetal tissues was examined in fetal sheep with normal and restricted placental size.Concentrations of IGF-I and -II proteins were measured in arterial blood samples collected from fetal sheep with normal and restricted placental size at 120 and I27 days gestation (term=150 days), via indwelling catheters.Concentrations of IGF-I in fetal blood at l2O and lZ7 days gestation correlated positively with fetal weight, placental weight and the weights of individual fetal tissues, measured at 130 days gestation.Fetal plasma IGF-I was positively related to fetal arterial blood pO2 and blood glucose at both gestational ages.In contrast, concentrations of IGF-II were related to fetal weight, placental weight and to fetal blood pO2 and glucose, at 127 days gestation, but not 120 days gestation.Therefore, the supply of substrates to the fetus is suggested as a regulator of the circulating concentration of IGF-I in late gestation, and very late in gestation of IGF-II, in the sheep fetus.These results are consistent with the suggestion that circulating IGFs may mediate, in part, the effect of altered substrate supply on growth of the fetal sheep.However, changes in the concentrations of the IGF proteins in fetal blood may be the result of altered production at one or more tissue sites, as many fetal tissues and the placenta contain IGF-I and -II mRNAs.To determine whether altered fetal growth was associated with altered expression of the genes for IGF-I or IGF-II in fetal tissues, IGF-I and -II mRNAs were IX measured in tissues from a further group of normal and growth-retarded fetal sheep at l2l days gestation.IGF-I mRNA was detected in the ovine placenta and all six fetal tissues examined (liver, lung, quadriceps muscle, heart, kidney, cerebellum)' IGF-II mRNA was not detected in fetal sheep cerebellum, but was present in placenta and in the other fetal tissues examined.The highest relative abundance of IGF-I mRNA was observed in skeletal muscle and liver, while IGF-II mRNA was most abundant in kidney and lung.'Whenestimates were made of the total amount of IGF mRNAs in fetal tissues, using tissue mass, liver and muscle were identified as quantitatively major sites of IGF-I production, while skeletal muscle, placenta and lung were indicated as major sites of IGF-II synthesis.The relative abundance of IGF-I mRNA was reduced in skeletal muscle, kidney and lung of growth-retarded fetal sheep.IGF-I mRNA abundance in fetal liver, skeletal muscle and kidney correlated positively with fetal plasma IGF-I, implicating these tissues as potential sources of circulating IGF-I in utero.Therefore, altered production of IGF-I at a number of tissue sites in the growth-retarded fetus may contribute to retarded fetal growth, either through reduced local actions and./or as a consequence of reduced circulating levels.In fetal liver, IGF-I pRNA abundance correlated positively with fetal arterial blood pO2.However, plasma insulin, but not plasma glucose was related to hepatic IGF-I mRNA abundance.Therefore, restricted nutrient supply may regulate IGF-I production in fetal liver, at least in part via changes in plasma insulin.These results are consistent with regulation of expression of the IGF-I gene in fàtal sheep tissues by substrate supply.In contrast to IGF-I, the abundance of IGF-II mRNA was not altered in any of the fetal tissues examined at I2O days gestation in the growth-retarded fetus.No associations were observed between IGF-II mRNA abundance in fetal tissues and IGF-II protein concentrations in fetal blood, and it is possible that a number of fetal tissues may be sources of IGF-II protein in fetal blood.Furthermore, no associations were observed between the concentrations of substrates in fetal blood and expression of IGF-II in fetal tissues, suggesting that at this gestational stage, substrate supply is not an important regulator of IGF-II production.X Muscle and liver were indicated as potential sources of circulating IGF-I in the fetus.In the adult, negative feedback regulation of hepatic IGF-I production is suggested.Therefore, to determine whether IGF-I regulates IGF-I or -II gene expression in the fetus, the effect of intravenous infusion of IGF-I into the fetal sheep on the abundance of IGF-I and -II mRNAs in fetal liver and skeletal muscle was determined.Recombinant human IGF-I (26uglkglhr) or saline was infused continuously into the fetal tarsal vein from l2O to 130 days gestation.plasma IGF-I was increased by approximately three-fold by infusion of IGF-I into the fetus, but plasma IGF-II concentrations did not change.Infusion of IGF-I reduced the abundance of IGF-I and -II mRNAs in fetal liver by approximately 507o, but, had no effect on IGF-I and -II mRNAs in skeletal muscle.This suggests that IGF-I inhibits the expression of both IGF-I and -II genes in fetal liver, but not in fetal muscle.However the concentration of insulin in fetal blood was also reduced by IGF-I infusion, suggesting that the inhibition of hepatic IGF- I expression may be mediated indirectly through insulin.In summary, these current studies indicate that retarded fetal growth in sheep, associated with restricted supply of substrates to the fetus, is accompanied by reduced concentrations of IGF- I in fetal blood and decreased production of IGF-I in several major fetal tissues.This suggests that both altered endocrine and autocrine/paracrine actions of the IGFs may contribute to retarded growth of the fetus when placental supply of substrates is limited.Although many tissues may contribute to circulating IGF-I proteins in the fetus, liver, and possibly muscle, were suggested as likely sources of IGF-I protein in fetal sheep blood and in the former IGF-I expression may be subject to negative feedback regulation.In contrast, concentrations of IGF-II in fetal blood are reduced in later gestation only, suggesting that any role of IGF-II in mediating the influence of placental substrate supply on fetal growth occurs very late in gestation.
Author: Kind, Karen Lee
Institution: The University of Adelaide
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2659273292