Elsevier

Brain Research

Volume 846, Issue 2, 6 November 1999, Pages 236-242
Brain Research

Research report
Maternal nutrient restriction (48 h) modifies brain corticosteroid receptor expression and endocrine function in the fetal guinea pig

https://doi.org/10.1016/S0006-8993(99)02058-2Get rights and content

Abstract

Modification of the fetal environment has been shown to program hypothalamo-pituitary-adrenal (HPA) development. Altered expression of brain corticosteroid receptors is thought to be central to this process. In the fetal guinea pig, rapid development of glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) occurs in concert with rapid brain growth. Since nutrient availability has been associated with programming of endocrine function, we hypothesized that 48 h of maternal nutrient deprivation during rapid brain growth modifies the fetal endocrine environment and alters expression of GR and MR in the fetal brain. Pregnant guinea pigs were deprived of food (water available ad libitum) or fed normally on gestational days 50–51, and euthanized on gd52 (term=70 days). Nutrient deprivation caused intrauterine growth restriction (IUGR), though brain growth was protected. Fetal and maternal plasma cortisol was elevated in the deprived animals (p<0.001), though plasma adrenocorticotrophin (ACTH) was only elevated in maternal blood. In deprived fetuses, plasma thyroxin levels were significantly (p<0.001) lower than control. GR mRNA levels were significantly decreased in the hypothalamic paraventricular nucleus (PVN; p<0.05) and CA1/2 (p<0.01) region of the hippocampus in female fetuses, and in the hippocampal CA1/2 in male fetuses (p<0.01). In contrast, MR mRNA levels were not changed by nutrient deprivation. In conclusion, 48 h of nutrient deprivation, activates the maternal, but not the fetal HPA axis, and decreases GR mRNA but not MR mRNA levels in the developing hypothalamus and limbic system. These developmental perturbations may have an important impact on the trajectory of corticosteroid receptor development and therefore central glucocorticoid feedback regulation.

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.

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