Block BS, Schlafer DH, Wentworth RA, Kreitzer LA and Nathanielsz PW (1990) MA (1993)

No abstract

We examined the in situ localization of key steroidogenic enzymes in adrenal gland sections from midgestation (17-24 weeks) human fetuses and late gestation (130-142 days; term = 165 days) rhesus monkey fetuses. The rhesus monkey fetal adrenals were used as a model for the late gestation human fetal adrenal. The enzymes examined were cytochrome P450 cholesterol side-chain cleavage (P450scc), cytochrome P450 17 alpha-hydroxylase/17,20-lyase (P450c17), and 3 beta-hydroxysteroid dehydrogenase/isomerase (3 beta HSD). In human fetal adrenals, P450scc and P450c17 proteins and mRNAs were detected only in fetal zone (innermost cortical zone) and transitional zone (between the fetal and definitive zone) cells, not in definitive zone cells. Expression of 3 beta HSD was not detected in any cortical zone cells in midgestation human fetal adrenals. In rhesus monkey fetal adrenals, a similar pattern of P450scc and P450c17 expression was observed in the fetal and transitional zones. In the definitive zone cells of rhesus monkey fetal adrenals, expression of both P450scc and 3 beta HSD was detected. In addition, low levels of 3 beta HSD expression could be detected in some transitional zone cells. P450c17 expression was lacking in definitive zone cells from rhesus monkey fetal adrenals. These data suggest that early in gestation, cortisol is not produced by the human fetal adrenal cortex in vivo (because it does not express 3 beta HSD), whereas androgen production occurs in the transitional and fetal zones (which express P450scc and P450c17). Later in gestation, the definitive zone may produce minearlocorticoids (because it expresses P450scc and 3 beta HSD, but lacks P450c17), and the transitional zone may produce glucocorticoids (it expresses P450scc, P450c17, and 3 beta HSD), whereas the fetal zone continues to produce androgens. Thus, late in gestation the functional zonation of the human fetal adrenal cortex may be similar to that of the adult, with the definitive zone being analogous to the nascent zona glomerulosa, the transitional zone analogous to the zona fasciculata, and the fetal zone analogous to the zona reticularis.

1. A range of epidemiological studies has shown that poor intra-uterine growth is associated with an increased prevalence of cardiovascular disease, non-insulin-dependent diabetes mellitus and the Metabolic syndrome in adult life. 2. Because these associations are independent of adult lifestyle or current size, it has been postulated that a reduced intra- uterine nutrient supply perturbs fetal growth and, concomitantly, alters or programmes the structure and function of developing systems. 3. A reduced fetal nutrient supply may be a consequence of poor placental function or inadequate maternal nutrient intake. 4. It has been proposed that one outcome of either a suboptimal placental or maternal nutrient supply is exposure of the fetus to excess glucocorticoids, which act to restrict fetal growth and to programme permanent changes in the cardiovascular, endocrine and metabolic systems. 5. While a range of studies in the rat has investigated the impact of maternal undernutrition on arterial blood pressure in the offspring, there have been relatively few studies in species, such as the sheep, in which the responses of the cardiovascular and neuroendocrine systems to intra-uterine undernutrition can be measured before birth. 6. The present review summarizes recent evidence that poor placental function or inadequate maternal nutrition each results in an increased exposure of fetal sheep tissues to glucocorticoids and, in specific, changes in the regulation of fetal arterial blood pressure. 7. These studies are important in determining how the timing, type and duration of fetal nutrient restriction are each important in determining the nature of the fetal neuroendocrine and cardiovascular adaptive responses and their pathophysiological sequelae in later life.

Previous studies in the primate fetal adrenal gland have indicated that the gland is comprised of three functional zones: 1) the inner fetal zone (FZ), which has the enzymes necessary for dehydroepiandrosterone sulfate (DHEAS) production beginning early in gestation; 2) the transitional zone (TZ), which possesses enzymes necessary for cortisol production; and 3) the outer, definitive zone (DZ), which appears to function as a reservoir of progenitor cells that may populate the remainder of the gland and does not acquire a steroidogenic phenotype with the capacity to produce mineralocorticoids until near term. The enzymes CYP21A2 (P450 21 hydroxylase, or P450c21), CYP11B1 (11beta hydroxylase or P450c11) and CYP11B2 (aldosterone synthase) are necessary for glucocorticoid and mineralocorticoid synthesis but have not been localized previously in an ontogenic manner in the primate fetal adrenal gland. Therefore, we used immunocytochemistry (ICC) to assess specific zonal localization and developmental regulation of CYP21A2 and CYP11B1/CYP11B2 in the human (13-24 weeks' gestation) and rhesus monkey (109 d-term) fetal adrenal gland. In the fetal rhesus, ICC was performed with and without metyrapone administration to the fetus to assess the effects of endogenously increased fetal ACTH. In the human fetal adrenal, CYP21A2 immunoreactivity (IR) was present in only a few isolated cells in the DZ but was detectable in almost all cells in the TZ and FZ. In the fetal rhesus, CYP21A2-IR was present in cells throughout the DZ and TZ and, to a lesser degree, in the FZ. Staining intensity increased with advancing gestational age and was up-regulated in the DZ and TZ, but not the FZ, of the metyrapone-treated fetuses. In the human fetal adrenal gland, CYP11B1/CYP11B2-IR was absent in the DZ but present in the TZ and FZ. In the fetal rhesus monkey adrenal, CYP11B1/CYP11B2-IR was present in all cells of the TZ and FZ but was absent from the DZ until near term. After metyrapone, CYP11B1/CYP11B2-IR was induced in the DZ and was up-regulated in the TZ and FZ. Taken together, these data indicate that in the primate fetal adrenal gland, the FZ has the capacity to synthesize DHEA and DHEAS beginning early in development, the TZ has the capacity to synthesize cortisol after midgestation, and the DZ has the capacity to synthesize mineralocorticoids, but not until near term. The spatial localization of steroid metabolizing enzymes and steroid products in the human and rhesus monkey fetal adrenal suggests analogies of the three functional zones of the fetus (DZ, TZ, and FZ) to their adult counterparts (zona glomerulosa, zona fasciculata, and zona reticularis) and their steroid products (mineralocorticoids, glucocorticoids and androgens, respectively), although the reason for the presence of CYP11B1/CYP11B2- and CYP21A2-IR in the FZ remains to be elucidated.