Renal morphology in adult control and prenatally dexamethasone-treated animals Representative photomicrographs of the renal cortex from two animals from the control group (CON; A and B) and four animals prenatally treated with dexamethasone (DEX; C-F); Tissues shown in A and E were stained with haematoxylin and eosin and those in B, C, D and F were stained with Masson trichrome. In three out of four DEX animals (C, D and F) the proximal tubules (large arrows) were markedly dilated and enlarged. There was no noticeable collagen accumulation in the glomeruli of any animal, but excess collagen can be seen in the tubular interstitium and the periadventitia of cortical vessels (small arrows). Bar represents 50 mm.

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....

It is well established that erythropoiesis occurs first in the yolk sac, then in the liver, subsequently moving to the bone marrow and, in rodents, the spleen during development. The origin of the erythropoietic precursors and some factors suggested to be important for the changing location of erythropoiesis are discussed in this review. Until recently, the major site of erythropoietin (Epo) production in the fetus was thought to be the liver, but studies have shown now that the Epo gene is expressed strongly in the fetal kidney, even in the temporary mesonephros. The metanephric Epo mRNA is upregulated by anemia, downregulated by glucocorticoids, and contributes substantially to circulating hormone levels in hemorrhaged ovine fetuses. Other sites of Epo and Epo receptor production, likely to have important actions during development, are the placenta and the brain.

The relaxin knockout (rlx -/-) mouse was used to assess the effect, during pregnancy, of relaxin with regard to water, collagen content, growth, and morphology of the nipple (N), vagina (V), uterus, cervix (C), pubic symphysis (PS), and mammary gland (MG). The results presented here indicate that during pregnancy, relaxin increases the growth of the N, C, V, and PS. Large increases in water content in the PS (20%) occurred in pregnant (Day 18.5) wild-type (rlx +/+) mice but not in rlx -/- animals. This indicates that in the PS, relaxin might increase the concentration of a water-retaining extracellular matrix component (hyaluronate). In the pregnant rlx +/+ mouse, collagen content decreased significantly in the N and V but not in other tissues. There were no significant changes in the rlx -/- mouse. This contrasts with findings in the rat, in which relaxin has been found to cause decreases in collagen concentrations in the V, C, and PS. Histological analysis showed that the collagen stain was more condensed in the tissues (V, C, PS, N, and MG) of rlx -/- mice than in those of rlx +/+ mice. This phenomenon indicates that the failure of collagen degradation and lack of growth in the N underlie the inability of the rlx -/- mice to feed their young, as reported previously. Vaginal and cervical luminal epithelia, which proliferated markedly in the rlx +/+ pregnant mice, remained relatively atrophic in the rlx -/- mice. As proliferation and differentiation of uterine and vaginal epithelia are thought to be induced by a paracrine stromal factor that acts upon estrogen stimulation, our results indicate that relaxin may be this paracrine factor.

This review highlights the important roles the mesonephros may play in development. In the ovine fetus it is an excretory and endocrine organ and may contribute to the formation of normal gonads and adrenals. The metanephros of the ovine fetus has the important function of providing large quantities of dilute urine for the maintenance of amniotic and allantoic fluid volumes, essential for normal placentation and development.

During pregnancy, in women and the rat, there is a resetting of the plasma osmolality-arginine vasopressin relationship (P(osmol)/PAVP) such that a decrease in P(osmol) is maintained without suppression of PAVP. This occurs at a time when relaxin is detectable in plasma. The hypothesis tested here was that relaxin could alter the P(osmol)/PAVP in the non-pregnant rat. One group of ovariectomized rats (n = 15) was treated for 7 days with intravenous synthetic human relaxin (10 micrograms/h) in 10 microliters 0.9% (w/v) NaCl. Controls were two groups of rats either with no treatment (n = 15) or treated with vehicle alone (n = 15). One-third of each group received hypertonic saline (0.4 mol NaCl/l, 2 ml/100 g body weight i.p.) on day 7, and one-third were deprived of water for the final 24 h. All rats were killed by decapitation and blood was collected rapidly (< 40 s) for hormone and osmolality assays. The P(osmol) in all relaxin-treated rats was significantly (P < 0.001) lower than that in both control groups, but the PAVP was unchanged. The log PAVP/P(osmol) regression line was significantly shifted in elevation (P < 0.001) but not in slope. Thus treatment of ovariectomized rats with relaxin caused changes in fluid balance which mimic those occurring in normal pregnancy.

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Numerous epidemiological studies, together with mounting evidence from studies in animals, point to a correlation between an adverse intrauterine environment and the early onset of cardiovascular and metabolic diseases later in life. We were the first to show that sheep exposed to dexamethasone (0.28 mg.kg-1.day-1 for only 2 days) at the end of the first month of pregnancy (PTG1), but not those exposed at the end of the second month of pregnancy (PTG2), had a higher basal mean arterial pressure (MAP) 19 months after birth. In the present study we report the MAP, cardiovascular haemodynamics and baroreflex sensitivity in these animals at 40 months of age. MAP in the PTG1 group was significantly higher than in the control group (91+/-1 mmHg and 81+/-1 mmHg respectively; P<0.001) and also when compared with the PTG2 group (82+/-1 mmHg; P<0.001). There was a significant increase in cardiac output in the PTG1 group compared with the control group (108+/-2 and 96+/-4 ml.min-1.kg-1 respectively; P<0.05). The increase in cardiac output in the PTG1 group was due to an increase in stroke volume (1.82+/-0.08 ml.kg-1. beat-1, compared with 1.46+/-0.06 ml.kg-1.beat-1 in the control group; P<0.05), but not in heart rate. In the hypertensive group of animals (PTG1), there was a rightward shift of the baroreflex curve. In group PTG2 (the normotensive group of animals), a lower gain was found before and during propranolol treatment. The decrease in gain of the baroreflex was not associated with changes in heart rate range, suggesting an impairment in the central processing of the baroreceptor signals. Thus sheep fetuses exposed to dexamethasone for only 2 days at the end of the first month of gestation have high blood pressure (dependent upon the increase in cardiac output) and a reset of the baroreflex at 40 months of age. Animals that have received prenatal dexamethasone closer to mid-gestation, although normotensive with normal cardiac output, showed an altered baroreceptor-heart rate response.