Adverse environmental conditions during early life are known to determine adult metabolic phenotype in laboratory species and human populations. However, less is known about developmental programming of adult metabolic phenotype in livestock, given their size and longevity compared to laboratory animals. As maternal and/or fetal glucocorticoid (GC) concentrations rise in stressful conditions during pregnancy, GCs may act as a common mechanism linking early-life environmental conditions to the subsequent metabolic phenotype. This review examines prenatal and longer-term postnatal programming of metabolism by early-life GC overexposure in livestock species with a particular emphasis on sheep. It examines the effects of both cortisol, the natural glucocorticoid and more potent synthetic GCs used clinically to treat threatened pre-term delivery and other conditions during pregnancy. It considers the effects of early- life GC overexposure on the metabolism of specific feto-placental and adult tissues in relation to changes in the growth trajectory, other metabolic hormones and in the functioning of the hypothalamic–pituitary–adrenal axis itself. It highlights the role of GCs as maturational and environmental signals in programming development of a metabolic phenotype fit for survival at birth and future homeostatic challenges. However, the ensuing metabolic phenotype induced by early GC overexposure may become inappropriate for the prevailing postnatal conditions and lead to metabolic dysfunction as functional reserves decline with age. Further studies are needed in livestock to establish whether the metabolic outcomes of early-life GC overexposure are sex-linked, more pronounced in old age and inherited transgenerationally in these species.

Prenatal glucocorticoid overexposure causes adult metabolic dysfunction in several species but its effects on adult mitochondrial function remain largely unknown. Using respirometry, this study examined mitochondrial substrate metabolism of fetal and adult ovine biceps femoris (BF) and semitendinosus (ST) muscles after cortisol infusion before birth. Physiological increases in fetal cortisol concentrations pre-term induced muscle- and substrate-specific changes in mitochondrial oxidative phosphorylation capacity in adulthood. These changes were accompanied by muscle-specific alterations in protein content, fibre composition and abundance of the mitochondrial electron transfer system (ETS) complexes. In adult ST, respiration using palmitoyl-carnitine and malate was increased after fetal cortisol treatment but not with other substrate combinations. There were also significant increases in protein content and reductions in the abundance of all four ETS complexes, but not ATP synthase, in the ST of adults receiving cortisol prenatally. In adult BF, intrauterine cortisol treatment had no effect on protein content, respiratory rates, ETS complex abundances or ATP synthase. Activity of citrate synthase, a marker of mitochondrial content, was unaffected by intrauterine treatment in both adult muscles. In the ST but not BF, respiratory rates using all substrate combinations were significantly lower in the adults than fetuses, predominantly in the saline-infused controls. The ontogenic and cortisol-induced changes in mitochondrial function were, therefore, more pronounced in the ST than BF muscle. Collectively, the results show that fetal cortisol overexposure programmes mitochondrial substrate metabolism in specific adult muscles with potential consequences for adult metabolism and energetics.

Prenatal glucocorticoid overexposure has been shown to programme adult cardiovascular function in a range of species, but much less is known about the long-term effects of neonatal glucocorticoid overexposure. In horses, prenatal maturation of the hypothalamus–pituitary–adrenal axis and the normal prepartum surge in fetal cortisol occur late in gestation compared to other precocious species. Cortisol levels continue to rise in the hours after birth of full-term foals and increase further in the subsequent days in premature, dysmature and maladapted foals. Thus, this study examined the adult cardiovascular consequences of neonatal cortisol overexposure induced by adrenocorticotropic hormone administration to full-term male and female pony foals. After catheterisation at 2–3 years of age, basal arterial blood pressures (BP) and heart rate were measured together with the responses to phenylephrine (PE) and sodium nitroprusside (SNP). These data were used to assess cardiac baroreflex sensitivity. Neonatal cortisol overexposure reduced both the pressor and bradycardic responses to PE in the young adult males, but not females. It also enhanced the initial hypotensive response to SNP, slowed recovery of BP after infusion and reduced the gain of the cardiac baroreflex in the females, but not males. Basal diastolic pressure and cardiac baroreflex sensitivity also differed with sex, irrespective of neonatal treatment. The results show that there is a window of susceptibility for glucocorticoid programming during the immediate neonatal period that alters cardiovascular function in young adult horses in a sex-linked manner.

We have reported that blood pressure was elevated in 3-month-old rats whose mothers were Fe-restricted during pregnancy. These animals also had improved glucose tolerance and decreased serum triacylglycerol. The aim of the present study was to determine whether these effects of maternal nutritional restriction, present in these animals at 3 months of age, can be observed in the same animals in later life. Pulmonary and serum angiotensin converting enzyme (ACE) concentrations were also measured to investigate whether the renin–angiotensin system was involved in the elevation of blood pressure observed in the offspring of Fe-restricted dams. Systolic blood pressure was higher in the offspring of Fe-restricted dams at 16 months of age. Heart and kidney weight were increased as a proportion of body weight in the offspring of Fe-restricted dams. The pulmonary ACE concentration was not significantly different between the groups. The serum ACE concentration was significantly elevated in the offspring of Fe-restricted dams at 3 but not 14 months of age. There was a strong correlation between serum ACE levels at 3 and 14 months of age. Glucose tolerance and serum insulin were not different between the maternal diet groups. Serum triacylglycerol tended to be lower in the offspring of Fe-restricted dams. There were no differences in serum non-esterified fatty acids or serum cholesterol between the maternal diet groups. This study provides further evidence that maternal nutrition has effects on the offspring that persist throughout life. At 16 months of age, the elevation of blood pressure in Fe-restricted offspring does not appear to be mediated via changes in ACE levels. Both cardiac hypertrophy and decreased serum triacylglycerol have also been observed in Fe-restricted fetuses, suggesting that these changes may be initiated in utero.

Uptakes of oxygen, glucose and lactate by the gravid uterus, fetus and uteroplacental tissues were measured in chronically catheterized pregnant ponies and their fetuses at mid- and late gestation (term 335 days). Rates of O2 uptake by the gravid uterus, fetus and uteroplacental tissues were significant at both gestational ages and were 2- to 3-fold higher in late gestation than the mid-gestation values of 3338 ± 794, 1352 ± 258 and 2035 ± 602 µmol min-1, respectively (n = 4). Similarly, there were significant uptakes of glucose by the gravid uterus, fetus and uteroplacental tissues at both mid- and late gestation. However, unlike O2 uptake, glucose uptake by the uterus and uteroplacental tissues did not increase between mid- and late gestation. No significant uptakes or outputs of lactate were observed by the uterus or uteroplacental tissues at either gestational age, although there was a significant umbilical uptake of lactate in late but not mid-gestation. There was no change in the distribution of uterine O2 uptake between the fetus and uteroplacental tissues with increasing gestational age. The uteroplacental tissues accounted for about 50 % of the uterine O2 uptake at both gestational ages. In contrast, the proportion of the uterine glucose uptake used by the uteroplacental tissues decreased from 73.2 ± 2.1 % (n = 5) at mid-gestation to 61.1 ± 1.9 % (n = 4, P < 0.02) in late gestation. The gestational changes in uteroplacental carbohydrate metabolism in the mare differ from those seen in the ewe and may have important consequences for the duration and outcome of pregnancy in the mare. Experimental Physiology (2000) 85.5, 539-545.