Differential Effects of Placental Restriction on IGF‐II, ACTH Receptor and Steroidogenic Enzyme mRNA Levels in the Foetal Sheep Adrenal

Abstract

We have investigated the effects of restriction of placental growth on foetal adrenal growth and adrenal expression of mRNAs for Insulin-like Growth Factor II (IGF-II), the IGF binding protein IGFBP-2, Steroidogenic Factor 1 (SF-1) and adrenocorticotrophic hormone (ACTH) receptor (ACTH-R) and the steroidogenic cytochrome P-450 enzymes: cholesterol side chain cleavage (CYP11A1), 17alpha-hydroxylase (CYP17) and 21-hydroxylase (CYP21A1); and 3beta-hydroxysteroid dehydrogenase/Delta5Delta4 isomerase (3betaHSD). Endometrial caruncles were removed from non-pregnant ewes before mating (placental restriction group; PR). The total adrenal: foetal weight ratio was higher in PR (n=6 foetuses) than in control foetuses (n=6 foetuses). There was no difference in plasma ACTH concentrations between the PR and control foetuses between 130 and 140 days gestation. Adrenal IGF-II mRNA levels were lower (P<0.05) in the PR group, however, adrenal IGFBP-2 mRNA levels were not different between the PR and control groups. Adrenal ACTH-R mRNA levels were also lower whilst CYP11A1 mRNA levels were increased (P<0.005) in the PR group. We conclude that foetal adrenal growth and steroidogenesis are stimulated as a consequence of foetal growth restriction and that factors other than ACTH are important in foetal adrenal activation during chronic, sustained hypoxaemia.

Impact of chronic hypoxemia on blood flow to the brain, heart, and adrenal gland in the late-gestation IUGR sheep fetus

“…Despite the increase in relative adrenal weight, there is a decrease in adrenal steroidogenic acute regulatory protein expression in the PR fetus at 141 days gestation (17). However, there is an increase in adrenal mRNA expression of cytochrome P-450 11A1 (CYP11A1), but not cytochrome P-450 17 (CYP17) and cytochrome P-450 21A (CYP21A), suggesting that steroidogenic capacity may be increased in the adrenal of the chronically hypoxemic PR fetus (74). It is of interest that the adrenal weight is associated with plasma cortisol concentration at the time of the blood flow measures in these fetuses, despite the lack of increase in plasma cortisol concentrations in the PR fetuses, which may be due to the gestational age studied.…”

Periconceptional undernutrition in normal and overweight ewes leads to increased adrenal growth and epigenetic changes in adrenal IGF2/H19 gene in offspring

“…There are, however, conflicting data on the role that IGFs may play in vivo on adrenal growth and steroidogenesis in early life. We have previously shown that in growth‐restricted fetal sheep, a decrease in adrenal IGF2 mRNA expression is also associated with an increase in fetal adrenal weight (37). An alternative possibility given the data from the present study is that intra‐adrenal IGF2 may act in vivo to inhibit, rather than stimulate, adrenal growth.…”

Sex‐ and age‐specific effects of nutrition in early gestation and early postnatal life on hypothalamo‐pituitary‐adrenal axis and sympathoadrenal function in adult sheep

“…In contrast to handled rats, however, cortisol output in postnatally undernourished female sheep was not concomitantly reduced, suggesting an enhanced adrenocortical responsiveness to the prevailing ACTH concentrations in these groups. Further studies are required to determine whether this is due to increases in steroidogenic enzymes and/or the ACTH receptor density in the cortex, which have both been shown to be affected by nutritional/stressful stimuli (Ross et al 2000; Edwards et al 2002).…”