Research reportMaternal nutrient restriction (48 h) modifies brain corticosteroid receptor expression and endocrine function in the fetal guinea pig
Introduction
Prenatal and postnatal environmental manipulation has permanent effects on hypothalamo-pituitary-adrenal (HPA) function in developing rats 1, 11, 30, 40. Recently, it has been shown that these changes are linked to alterations in glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) expression in the limbic system 5, 21, 22. Since the hippocampus contains high levels of corticosteroid receptors and is an important regulator of glucocorticoid negative feedback 11, 15, changes in receptor expression will potentially alter negative feedback thresholds within the HPA axis. This can ultimately lead to long-term changes in the regulation of plasma adrenocorticotrophin (ACTH) and glucocorticoid concentrations.
Short periods (48 h) of nutrient restriction have been shown to cause intra-uterine growth restriction (IUGR) in rapidly growing fetal guinea pigs, as well as to alter pituitary-adrenocortical and pituitary-thyroid activity [16]. However, to date, no studies have investigated the impact of short-term nutrient restriction on development of corticosteroid receptor systems in the fetal brain of any species. We have recently demonstrated that extensive neuroendocrine maturation and rapid development of the GR and MR systems occurs during late fetal life in the guinea pig [24]. Similar rapid brain growth, which is linked to neuroendocrine development also occurs in late fetal life in primates and humans 12, 13. In the present study, we hypothesize that fetal endocrine activity and the development of brain corticosteroid receptor systems are profoundly influenced by short periods of nutrient deprivation in the guinea pig; a species where the majority of brain development occurs in utero. Therefore, we have examined the acute effects of nutrient restriction, during the most rapid phase of neuroendocrine/brain development, on systems that modulate glucocorticoid feedback on the HPA axis.
Section snippets
Animals and treatments
Female guinea pigs were mated in our animal facility using a technique developed at the Nuffield Institute for Medical Research, Oxford, UK [14]. This method produces accurately time-dated pregnant guinea pigs. These studies were performed according to protocols approved by the Animal Care Committee at the University of Toronto, in accordance with the Canadian Council for Animal Care. Pregnant guinea pigs were deprived of all food for 48 h on gd50 (n=7), or allowed to feed normally (control, n
Results
The effects of nutritional deprivation on fetal body and organ weights as well as organ to bodyweight ratios are shown in Table 1. Nutritional deprivation during the most rapid period of brain development caused a significant reduction (10%; p<0.007) in fetal body weight compared to controls. IUGR was accompanied by a significant (p<0.0005) increase in brain to bodyweight ratio indicating brain `sparing'. Interestingly, there was a significant (p<0.007) decrease in kidney weight in deprived
Discussion
In the present study, we have shown, for the first time, that 48 h of nutrient deprivation causes a significant region-specific reduction in GR mRNA in areas associated with the modulation of glucocorticoid feedback on the HPA axis. Interestingly, there was no effect on MR mRNA. We have also shown that maternal nutrient deprivation results in an elevation of fetal plasma cortisol concentrations, which are not associated with, increased levels of fetal plasma ACTH, suggesting transfer of
Acknowledgements
This work was supported by the Natural Sciences and Engineering Research Council of Canada and the Banting Foundation, Toronto.
References (40)
- et al.
Effects of early experience on adrenocortical reactivity
Physiol. Behav.
(1969) - et al.
Effects of short-term dexamethasone treatment during pregnancy on the development of the immune system and the hypothalamo-pituitary adrenal axis in the rat
J. Neuroimmunol.
(1995) - et al.
Fetal nutrition and cardiovascular disease in adult life
Lancet
(1993) - et al.
Comparative aspects of the brain growth spurt
Early Hum. Dev.
(1979) - et al.
Studies on the growth of the fetal guinea pig. The effects of nutritional manipulation on prenatal growth and plasma somatomedin activity and insulin-like growth factor concentrations
J. Dev. Physiol.
(1990) - et al.
Protein intake in pregnancy, placental glucocorticoid metabolism and the programming of hypertension in the rat
Placenta
(1996) Dynamic changes in glucocorticoid and mineralocorticoid receptor mRNA in the developing guinea pig brain
Dev. Brain Res.
(1998)Does prenatal stress impair coping and regulation of hypothalamic–pituitary–adrenal axis
Neurosci. Biobehav. Rev.
(1997)- et al.
Threshold of hormonal and biophysical responses to acute hypoxemia in fetal sheep at different gestational ages
Can. J. Physiol. Pharmacol.
(1990) - M.H. Andrews, F. Dean, S.G. Matthews, Hypothalamic glucocorticoid receptor and heat shock protein 70 expression during...