DEXAMETHASONE IN THE LAST WEEK OF PREGNANCY ATTENUATES HIPPOCAMPAL GLUCOCORTICOID RECEPTOR GENE-EXPRESSION AND ELEVATES BLOOD-PRESSURE IN THE ADULT OFFSPRING IN THE RAT

Human epidemiological data show a strong association between low birth weight and hypertension in adulthood, an effect that has been ascribe d to 'fetal programming'. In rats, fetoplacental exposure to maternall y administered dexamethasone throughout gestation reduces birth weight and produces hypertensive adult offspring, though the mechanism is un clear. Pre- and postnatal stress programmes hypothalamic-pituitary-adr enal (HPA) axis responses throughout the lifespan, an effect thought t o be mediated via permanent effects on glucocorticoid receptor (GR) an d/or mineralocorticoid receptor (MR) gene expression in the hippocampu s. Corticosteroids also have specific central effects on blood pressur e control mediated by GR and MR. This study investigated corticosteron e (CORT) responses to restraint stress and GR and MR gene expression i n areas of the brain postulated to mediate the central effects of cort icosteroids on (i) HPA axis suppression (hippocampus), and (ii) blood pressure (organ vasculosum of the lamina terminalis (OVLT), sub-commis sural organ, area postrema and nucleus tractus solitarius). Pregnant W istar rats received dexamethasone (100 mu g/kg . day(-1)) or vehicle o n days 15-20 of gestation. This reduced birth weight by 11 %. When the offspring were 16 weeks old, blood pressure was recorded directly and plasma CORT measured basally (AM) and after 30 min restraint. GR and MR mRNA expression were determined by in situ hybridization. Blood pre ssure was significantly elevated in the adult offspring of dexamethaso ne-treated pregnancies (dexamethasone 144 +/- 2/125 +/- 2 mm Hg vs. co ntrol 133 +/- 2.7/112 +/- 2.8 mm Hg; both p < 0.01). Offspring of dexa methasone-treated pregnancies had increased basal plasma CORT (155 +/- 29 nmol/l) compared to offspring of controls (79 +/- 15 nmol/l, p < 0 .05), but the CORT response to stress was similar. Hippocampal neurona l GR mRNA expression was significantly lower in the offspring of dexam ethasone-treated pregnancies (dentate gyrus 20% lower, CA1 15% lower; p < 0.01). Similarly, hippocampal MR gene expression was decreased in CA1 and CA2 by 24 and 25%, respectively (p < 0.05). No differences in GR or MR mRNA expression were found in the OVLT, subcommissural organ, area postrema or nucleus tractus solitarius. These findings suggest t hat glucocorticoid excess in the last trimester of rat pregnancy (i) i s sufficient to programme offspring hypertension; (ii) also increases basal plasma CORT levels, and (iii) permanently attenuates GR and MR m RNA expression in specific hippocampal subfields. This, if translated into protein, may reduce sensitivity to glucocorticoid feedback and th us contribute to the CORT excess. However, hypertension in this model is unlikely to be mediated by similar changes in GR or MR gene express ion in the examined areas of the brain putatively involved in the more direct central regulation of blood pressure.