Fetal dexamethasone exposure interferes with establishment of cardiac noradrenergic innervation and sympathetic activity.
Endogenous glucocorticoids provide natural differentiation signals for adrenergic neurons, and exposure to high exogenous steroid levels thus disrupts the timing of neuronal maturation. In the current study, pregnant rats were given 0.05, 0.2, or 0.8 mg/kg dexamethasone on gestational days 17, 18, and 19, and the effects on development of cardiac sympathetic function were assessed postnatally in the offspring. Dexamethasone produced a dose-dependent retardation of body and heart weight gains; at the highest dose, heart weight deficits were smaller than those for body weight, producing a relative cardiomegaly. The weight effects were accompanied by abnormalities of noradrenergic innervation, as assessed with measurements of norepinephrine levels and turnover. Norepinephrine levels were significantly reduced at all doses of dexamethasone, with the magnitude of effect exceeding that on heart or body weights; thus the levels were reduced even when corrected for tissue weight (ng norepinephrine/g heart weight). Norepinephrine turnover, a measure of neuronal impulse activity, showed delayed development at the lowest dose of dexamethasone and displayed profound suppression throughout development at the higher doses. Adverse effects of dexamethasone on norepinephrine turnover were still apparent in young adulthood, despite the recovery of weight variables to within 15% of normal values. In light of the release of steroids during maternal stress and the use of steroids in the therapy of neonatal respiratory distress, developing adrenergic neurons are likely to be targeted for adverse effects even when standard growth indices have normalized.
Bian
X
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Department of Pharmacology, Duke University Medical Center, Durham, North Carolina 27710.
Seidler
F J
FJ
Slotkin
T A
TA
D000014:Abnormalities, Drug-Induced / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D003907:Dexamethasone / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005318:Fetal Heart / Q000187:drug effects / Q000196:embryology / Q000294:innervation; D005865:Gestational Age; D006330:Heart Defects, Congenital / Q000139:chemically induced* / Q000196:embryology / Q000378:metabolism; D008431:Maternal-Fetal Exchange; D009638:Norepinephrine / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013564:Sympathetic Nervous System / Q000002:abnormalities / Q000187:drug effects / Q000378:metabolism
D003907:Dexamethasone; D009638:Norepinephrine