Programming Effects of Short Prenatal Exposure to Dexamethasone in Sheep

Abstract

Abstract-Recent studies have linked fetal exposure to a suboptimal intrauterine environment with adult hypertension. The aims of the present study were to see whether prenatal dexamethasone administered intravenously to the ewe between 26 to 28 days of gestation (1) resulted in high blood pressure in male and female offspring and whether hypertension in males was modulated by testosterone status, and (2) altered gene expression for angiotensinogen and angiotensin type 1 (AT 1 ) receptors in the brain in late gestation and in the adult. Basal mean arterial pressure (MAP) at 2 years of age was significantly higher in wethers exposed to prenatal dexamethasone (group D; 106Ϯ5 mm Hg, nϭ9) compared with the control group (group S; 91Ϯ3 mm Hg, nϭ8; PϽ0.01). Infusion of testosterone for 3 weeks had no effect on MAP in either treatment group. Key Words: brain Ⅲ glucocorticoids Ⅲ hypertension, experimental Ⅲ sheep E pidemiological evidence suggests that babies born small for gestational age have an increased incidence of adultonset diseases or dysfunction, including syndrome X (hypertension, non-insulin-dependent diabetes mellitus, and hyperlipidemia). [1][2][3] It is hypothesized that a suboptimal intrauterine environment during a critical stage of development permanently alters, or "programs," the development of fetal tissues. This may ensure the short-term survival of the fetus but also may bring adverse consequences in postnatal life.Animal models using maternal undernutrition or restriction of specific dietary components (iron, protein), either throughout pregnancy or during parts of gestation, have confirmed that restriction of fetal growth leads to elevated blood pressure in the progeny of rats. 4 -6 A second type of animal model has examined the long-term/programming effects caused by prenatal glucocorticoid exposure. When adult rats were exposed to large doses of carbenoxolone (an 11␤-hydroxysteroid dehydrogenase [HSD] inhibitor, which blocks placental inactivation of endogenous glucocorticoids) throughout gestation, offspring were of low birth weight and had high blood pressure. 7-9 The synthetic glucocorticoid dexamethasone, which is poorly metabolized by placental 11␤-HSD, given throughout rat pregnancy resulted in offspring with high blood pressure. 10 In the sheep, we 11 have shown that exposure to dexamethasone, for 2 days very early in gestation (at a mean age of 27 days of the 150-day gestation period) results in hypertensive female offspring by 3 to 4 months of age. This hypertension amplifies with age and is associated with an increased cardiac output. 12 By 7 years of age, these animals had developed left ventricular hypertrophy with reduced cardiac functional reserve. 13 In these studies, only female offspring were studied. However, in many models, the programming effects of the prenatal treatment are only seen in male offspring, 14 or they were more pronounced in male offspring compared with female offspring. 4 These studies proposed that programming, at least in some models, may be gender specific....

Sex differences in the fetal programming of hypertension

“…Male offspring in this model also demonstrate abnormalities in vascular function in isolated peripheral arteries (26). Blood pressure is also significantly higher in males than females in response to pharmacological levels of dexamethasone administered during early gestation in sheep (27,28). However, moderate protein restriction during gestation in the rat leads to marked increases in blood pressure in male offspring associated with a reduced nephron number (29).…”

Prolonged low-dose dexamethasone treatment, in early gestation, does not alter blood pressure or renal function in adult sheep

“…Previous studies in our laboratory demonstrated that highdose dexamethasone treatment administered to pregnant ewes (240 µg/kg maternal body weight per day), and thus their fetuses, for 2 days, early in pregnancy (26-28 days of gestation), has profound effects on adult cardiovascular function (Dodic et al 1998(Dodic et al , 1999(Dodic et al , 2001b(Dodic et al , 2002a. Also, this 2 day high-dose dexamethasone treatment causes significant changes in gene expression in the kidney, brain and hearts of twin ovine fetuses, killed at 130 days of gestation (Dodic et al 2001a, Hantzis et al 2001).…”

Comparative effects of dexamethasone on placental and foetal organ weights and some linear body measurements in Yankasa sheep and Sahel goats

“…Note the zona glomerulosa (thin arrow) and zona fasciculata (long arrow) and zona reticularis (thick arrow) H & E x100 the placenta into the foetal circulation and accesses foetal tissues may vary among species (Dodic et al, 2002). The placenta and foetal tissues in more susceptible species would have a greater proportion of glucocorticoid exposure following maternal dexamethasone treatment.…”