Glucocorticoid administration alters nuclear transcription factors in fetal rat brain: implications for the use of antenatal steroids.
A recent Consensus Conference endorsed antenatal steroid use in prematurity, but indicated the need for future work on molecular and cellular effects on the developing brain. In the current study, pregnant rats were given dexamethasone during late gestation, in doses spanning those recommended for use, and effects on nuclear transcription factors were evaluated. Within the first hour after a single dose of dexamethasone, and intensifying over 4 h, marked induction of brain c-fos was seen. With repeated administration, c-fos became suppressed in some brain regions, but remained elevated in others. Dexamethasone also elicited suppression of the AP-1 family of nuclear binding proteins, but with a slower time course than seen for c-fos induction. The magnitude of the effects of late gestational exposure to dexamethasone on these transcription factors was comparable to those seen when repeated doses were administered to midgestation embryos in the context of dysmorphogenesis. Similarly, the effects on brain c-fos expression were substantially greater than those in the liver, an archetypal glucocorticoid target tissue. These results indicate that even a single, low dose of glucocorticoids used in late gestation, can disrupt the transcription factors that regulate brain cell differentiation.
Slotkin
T A
TA
Box 3813, Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. t.slotkin@duke.edu
Zhang
J
J
McCook
E C
EC
Seidler
F J
FJ
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology* / Q000627:therapeutic use; D004622:Embryo, Mammalian / Q000378:metabolism*; D005260:Female; D005865:Gestational Age; D005938:Glucocorticoids / Q000494:pharmacology* / Q000627:therapeutic use; D008099:Liver / Q000378:metabolism; D011247:Pregnancy; D011295:Prenatal Care; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats / Q000196:embryology; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D014157:Transcription Factors / Q000378:metabolism*
D005938:Glucocorticoids; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D014157:Transcription Factors; D003907:Dexamethasone