GESTATIONAL AGE-DEPENDENT CHANGES IN THE LEVELS OF MESSENGER-RNAS ENCODING CORTISOL BIOSYNTHETIC-ENZYMES AND IGF-II IN THE ADRENAL-GLAND OFFETAL SHEEP DURING PROLONGED HYPOXEMIA

Hypoxemia represents a major stress for the fetus, and is associated w ith alterations and adaptations in cardiovascular, metabolic and endoc rine responses, which in turn may affect tissue growth and differentia tion. To determine the effects of hypoxemia on fetal adrenal activity and growth, we subjected sheep fetuses at days 126-130 and 134-236 (te rm 145 days) to reduced PaO2 by reducing the maternal fraction of oxyg en for 48 h (mean reduction of 6.8 mmHg), without change in arterial p H or PaCO2. This stimulus resulted in similar increases in the plasma immunoreactive ACTH response at both ages. Among adrenal steroids, pla sma cortisol (C21 Delta(4)) rose in both groups of animals, but plasma androstenedione (C19 Delta(4)) declined marginally, resulting in a pr onounced increase in the cortisol:androstenedione ratio in the plasma that was greater and more sustained in the older fetuses. In the young er fetuses, after 48 h of hypoxemia, there were no significant changes in mRNAs encoding steroidogenic enzymes in the fetal adrenal gland. H owever, in the older fetuses, hypoxemia resulted in significantly incr eased levels of mRNAs encoding P450(scc), P450(C21) and 3 beta-hydroxy steroid dehydrogenase, but not for P450(C17), in the fetal adrenal gla nd. Levels of IGF-II mRNA in the fetal adrenal gland fell in both grou ps of fetuses, and this response was greater at the later gestational age. We conclude that sustained hypoxemia is a potent stimulus which a ctivates adrenal steroidogenesis in the late gestation fetal sheep. Th e resultant increase in cortisol synthesis is associated with decrease d expression of adrenal IGF-II mRNA. We speculate that this relationsh ip might influence patterns of fetal organ growth and differentiative function in response to fetal stress such as hypoxemia.