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Development of glucocorticoid receptor regulation in the rat forebrain: Implications for adverse effects of glucocorticoids in preterm infants
Citation:
LAU, C. Development of glucocorticoid receptor regulation in the rat forebrain: Implications for adverse effects of glucocorticoids in preterm infants. BRAIN RESEARCH BULLETIN. Elsevier Science Ltd, New York, NY, 76(5):531-535, (2008).
Impact/Purpose:
Developmental origins of health and diseases in adulthood are an emerging concept that is finding applications in the field of toxicology. Cellular and molecular signals from the glucocorticoid hormone have been implicated to be one of the underlying mechanisms that confer to the etiology of the adult diseases. Our study examined the manners with which the glucocorticoids might exert their effects, at the hormone receptor level. Glucocorticoid receptor (GR) is typically auto-regulated by the hormone agonists, and will be down-regulated when concentrations of the agonist are elevated. Results from this study demonstrated, for the first time, that GR in the fetal rat brain was not down-regulated by exposure to the potent synthetic hormone, dexamethasone, in contrast to the robust down-regulation noted in the neonatal rat brain during postnatal development. Hence, there are critical windows during development where organs (such as brain) are particularly vulnerable to insults produced by excessive glucocorticoid hormones. In turn, these early insults may “re-program” the course of development and physiological set-points, leading to latent deleterious effects at adult age.
Description:
Glucocorticoids are the consensus treatment to avoid respiratory distress in preterm infants but there is accumulating evidence that these agents evoke long-term neurobehavioral deficits. Earlier, we showed that the developing rat forebrain is far more sensitive to glucocorticoid-induced disruption in the fetus than in the neonate. Feedback regulation of glucocorticoid receptors (GRs) is an essential homeostatic mechanism and we therefore examined the development of GR downregulation in the perinatal period. Pregnant rats or newborn pups were given dexamethasone daily (gestational days 17-19, postnatal days 1-3, or postnatal days 7-9), ranging from doses below that recommended for use in preterm infants (0.05 mg/kg) to therapeutic doses (0.2 or 0.8 mg/kg). Twenty-four hr after the last injection, we determined forebrain GR protein by Western blotting. Although postnatal dexamethasone treatment downregulated GRs at all doses, the fetal forebrain failed to show any decrement and instead exhibited slight GR upregulation. In controls, forebrain GR levels also showed a large increment over the course from late gestation through the second postnatal week, despite the fact that circulating glucocorticoid levels increase substantially during this period. Our results suggest that GR homeostasis develops primarily postnatally and that fetal inability to downregulate GRs in the face of exogenous glucocorticoid administration plays a role in the vulnerability of key neural circuits to developmental disruption. Since this developmental phase in the rat corresponds to the critical period in which glucocorticoids are used in preterm infants, adverse effects on brain development may be inescapable.
