Programming effects of short prenatal exposure to cortisol

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....

Programming Effects of Short Prenatal Exposure to Dexamethasone in Sheep

“…These findings are remarkable given that at the time of dexamethasone treatment, the ovine fetal brain is quite immature. 43 It is not known, however, if this very primitive brain expresses the genes for components of the angiotensin system. Components of the angiotensin system are present in the adult sheep brain, where they play a role in control of blood pressure, modulation of drinking behavior, salt appetite, sensory functions, memory and learning, and stimulation of pituitary hormone release.…”

Expression of glucocorticoid receptor, mineralocorticoid receptor, and 11β-hydroxysteroid dehydrogenase 1 and 2 in the fetal and postnatal ovine hippocampus: ontogeny and effects of prenatal glucocorticoid exposure

“…For quantitative PCR all primers were either designed using Primer 3.0 (PE Biosystems; for 11bHSD1 accession number 001009395) or have been previously used on ovine tissue (GR, MR, 11bHSD2, 18S; Dodic et al 2002. Primer sequences for hippocampal MR, GR, 11 bHSD1 and 2 and 18S sets are presented in Table 2.…”

“…The expression of hippocampal GR, MR, 11bHSD1, and 2 relative to the calibrator was evaluated using the expression 2 KDDC T . This method of analysis has been previously published using sheep RNA (Dodic et al 2002). All samples for each gene of interest were run in duplicate in a single assay.…”

Adverse prenatal environment and kidney development: implications for programing of adult disease

“…Protein restriction throughout pregnancy in the rat results in offspring that are born small, develop high blood pressure (Woods et al 2001), impaired renal function (Alwasel et al 2012), glucose intolerance (Ozanne et al 1996), and impaired fertility (Zambrano et al 2005), suggesting that sustained nutritional deficits throughout pregnancy can elicit a wide variety of long-term abnormalities (Woods et al 2001(Woods et al , 2005. Short-term infusions of glucocorticoids during early-or midgestation culminate in hypertension in both sheep (Dodic et al 2002) and rat offspring respectively (Ortiz et al 2003, Singh et al 2007a. Interestingly, the outcome is highly dependent upon the timing of exposure as the same level of glucocorticoid exposure did not result in hypertension when administered at other stages of development (Dodic et al 1999, Ortiz et al 2003.…”