Prenatal glucocorticoid overexposure causes permanent increases in renal erythropoietin expression and red blood cell mass in the rat offspring.

Glucocorticoids promote maturation of fetal systems, including erythropoiesis, in preparation for extrauterine life. However, recent studies have shown that prenatal glucocorticoid excess can cause long-term deleterious cardiometabolic and other consequences to the offspring. Here, we examined the effect of prenatal treatment with the synthetic glucocorticoid dexamethasone (DEX) during the last week of gestation on red blood cell (RBC) mass in the rat offspring. DEX-treated offspring at 9 months of age had significantly higher RBC count (9.4 ± 0.1 vs. 8.8 ± 0.2 × 10(12) liter; P = 0.02), hematocrit (50.0 ± 0.5 vs. 46.7 ± 0.7%; P=0.004), hemoglobin (17.3 ± 0.2 vs. 16.2 ± 0.2 g/dl; P = 0.02) and number of reticulocytes (258.2 ± 8.8 vs. 235.7 ± 5.6 × 10(9) liter; P = 0.04), compared with offspring of vehicle-treated control pregnancies. White blood cells and platelets were unaltered. Renal mRNA expression and plasma concentrations of erythropoietin, the main regulator of erythropoiesis, were increased by nearly 100% in both newborn and adult DEX-treated rats (P < 0.01). This increase was accompanied by marked elevation in renal expression of hepatocyte nuclear factor 4α mRNA, whereas other erythropoietin-regulating transcription factors, such as hypoxia-inducible factor 1, hypoxia-inducible factor 2, and GATA2 were unchanged. These data indicate that RBC mass can be programmed by prenatal glucocorticoid excess, and if extrapolatable to humans, provide a novel mechanism for fetal origins of polycythemia and its associated complications.