Hypoxemia represents a major stress for the fetus, and is associated with alterations and adaptations in cardiovascular, metabolic and endocrine responses, which in turn may affect tissue growth and differentiation. To determine the effects of hypoxemia on fetal adrenal activity and growth, we subjected sheep fetuses at days 126-130 and 134-136 (term 145 days) to reduced PaO 2 by reducing the maternal fraction of oxygen for 48 h (mean reduction of 6·8 mmHg), without change in arterial pH or PaCO 2 . This stimulus resulted in similar increases in the plasma immunoreactive ACTH response at both ages. Among adrenal steroids, plasma cortisol (C21 4 ) rose in both groups of animals, but plasma androstenedione (C19 4 ) declined marginally, resulting in a pronounced increase in the cortisol:androstenedione ratio in the plasma that was greater and more sustained in the older fetuses. In the younger fetuses, after 48 h of hypoxemia, there were no significant changes in mRNAs encoding steroidogenic enzymes in the fetal adrenal gland. However, in the older fetuses, hypoxemia resulted in significantly increased levels of mRNAs encoding P450 scc , P450 C21 and 3 -hydroxysteroid dehydrogenase, but not for P450 C17 , in the fetal adrenal gland. Levels of IGF-II mRNA in the fetal adrenal gland fell in both groups of fetuses, and this response was greater at the later gestational age. We conclude that sustained hypoxemia is a potent stimulus which activates adrenal steroidogenesis in the late gestation fetal sheep. The resultant increase in cortisol synthesis is associated with decreased expression of adrenal IGF-II mRNA. We speculate that this relationship might influence patterns of fetal organ growth and differentiative function in response to fetal stress such as hypoxemia.

Experiments were conducted in eight pregnant sheep to determine the effect on fetal growth of mechanical restriction of uterine blood flow (RUBF) between 120 days and 134 days gestation. Uterine blood flow measured in the middle uterine arteries was 40% less in RUBF animals compared with control animals at the end of the experimental period. There was no change in fetal blood gases, bodyweights, or organ weights between the two groups of animals. The rate of DNA synthesis in the right lobe of the liver was significantly less in RUBF animals (581 +/- 34 dpm micrograms-1 DNA) compared with control animals (845 +/- 44 dpm microgram-1 DNA). There was no difference in the rate of DNA synthesis in the left lobe of the liver or in any of the other organs examined. Autoradiographic examination of the placental cotyledons demonstrated that most DNA synthesis in the placenta was occurring in fetal trophoblastic cells and there was a 40% reduction in the nuclear-labelling index of placental trophoblast cells. These studies show that mild mechanical reductions in uterine blood flow in pregnant sheep results in the selective inhibition of growth in the right lobe of the fetal liver and the placental trophoblastic cells. The mechanism underlying this close association remains to be determined.

In the above paper, 1 the following error was published on p. 451 in the legend to Fig. 1

No abstract

Uteroplacental insufficiency is one of the major causes of fetal growth restriction (FGR) in developed countries. The pathophysiology is likely the result of fetal undernutrition due to the impairment of nutrient and substrate transfer from the mother to the fetus. Fetal undernutrition due to maternal undernutrition is not a major cause of FGR in developed countries compared to developing countries. However, FGR can be reproducibly created in experimental animals by maternal undernutrition, and is commonly utilized to study the pathophysiology of fetal undernutrition in the fetus and the placenta. The insulin-like growth factor (IGF) system is the principal growth factor involved in regulating normal fetal and placental growth and its aberrant expression is associated with the development of FGR. We hypothesized that placenta undergoes adaptive changes in pregnancies with maternal undernutrition, the effects of which are mediated by the IGF system. Methods: A mouse model of FGR was generated in CD-1 mice using maternal total caloric nutrient restriction. At 6.5 days of pregnancy, mice were randomly assigned to the control group (ad libitum diet) or global nutrient restriction (GNR) diet group (70% of predetermined food intake of each gestational day). FGR can be reproducibly induced in the fetuses without effect in litter size. Placentae were collected at 18.5 days and were fixed in 4% paraformaldehyde. Five mm tissue sections were prepared by standard techniques and were stained with hematoxylin & eosin for morphometry, PAS for glycogen staining, and immunohistochemistry against IGF-I and –II, IGFBP-1, -2 and –3 using specific antisera for cell-specific expression of the IGF system. The morphology of the placentae was analyzed using a computerized image analysis system. Results: Placentae were significantly smaller in FGR mice compared to controls (94±4 mg SEM vs 72±3 mg SEM). Preliminary results demonstrate changes in FGR mouse placentae tended to be a result of a reduction in spongiotrophoblast layer (p = 0.066, one-tailed t-test) while the labyrinthine trophoblast layer was maintained. Morphometric analysis of the labyrinth demonstrated an increase in the diameter of both maternal and fetal vessels with a reduction in the thickness of the interchorial layer. The IGF-I and –II, IGFBP-1, IGFBP-2 and IGFBP-3 immunoreactivity were all reduced in FGR placentae compared to the controls. Conclusion: These findings suggest that maternal nutrient restriction induces changes in the placenta that may potentially lead to improved nutrient and substrate transfer from mother to fetus, in an attempt to maintain fetal viability. However, these compensatory changes are not sufficient to maintain growth. These changes may result from the alteration of expression of the IGF system genes.