Gestational age-dependent changes in the levels of mRNAs encoding cortisol biosynthetic enzymes and IGF-II in the adrenal gland of fetal sheep during prolonged hypoxemia G A Braems 1,3 , V K M Han 2,3,4 and J R G Challis 1,3,4 1 Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada, 2 Departments of Pediatrics, Obstetrics and Gynecology, Anatomy and Cell Biology, and Biochemistry, University of Western Ontario, London, Ontario, Canada, 3 The Lawson Research Institute, St Joseph’s Health Center, London, Ontario, Canada and 4 MRC Group in Fetal and Neonatal Health and Development (Requests for offprints should be addressed to J R G Challis, Department of Physiology, Faculty of Medicine, 1 King’s College Circle, Room 3205/7, University of Toronto, Toronto, Ontario, Canada M5S 1A8) (G A Braems is now at Department of Obstetrics and Gynecology, University Hospital, Klinikstr. 32, D-35385, Giessen, Germany) Abstract Hypoxemia represents a major stress for the fetus, and is associated with alterations and adaptations in cardiovascu- lar, metabolic and endocrine responses, which in turn may affect tissue growth and differentiation. To determine the effects of hypoxemia on fetal adrenal activity and growth, we subjected sheep fetuses at days 126–130 and 134–136 (term 145 days) to reduced PaO 2 by reducing the maternal fraction of oxygen for 48 h (mean reduction of 6·8 mmHg), without change in arterial pH or PaCO 2 . This stimulus resulted in similar increases in the plasma immunoreactive ACTH response at both ages. Among adrenal steroids, plasma cortisol (C21 4 ) rose in both groups of animals, but plasma androstenedione (C19 4 ) declined marginally, resulting in a pronounced increase in the cortisol:andro- stenedione ratio in the plasma that was greater and more sustained in the older fetuses. In the younger fetuses, after 48 h of hypoxemia, there were no significant changes in mRNAs encoding steroidogenic enzymes in the fetal adrenal gland. However, in the older fetuses, hypoxemia resulted in significantly increased levels of mRNAs en- coding P450 scc , P450 C21 and 3-hydroxysteroid dehydro- genase, but not for P450 C17 , in the fetal adrenal gland. Levels of IGF-II mRNA in the fetal adrenal gland fell in both groups of fetuses, and this response was greater at the later gestational age. We conclude that sustained hypoxemia is a potent stimulus which activates adrenal steroidogenesis in the late gestation fetal sheep. The resultant increase in cortisol synthesis is associated with decreased expression of adrenal IGF-II mRNA. We speculate that this relationship might influence patterns of fetal organ growth and differentiative function in response to fetal stress such as hypoxemia. Journal of Endocrinology (1998) 159, 257–264 Introduction Hypoxemia is a potent stimulus which increases the activity of the hypothalamic–pituitary–adrenal (HPA) axis in the fetus. In response to short-term (60 min) hypox- emia, there are increases in fetal plasma concentrations of adrenocorticotrophin (ACTH), vasopressin and cortisol (Boddy et al. 1974, Rurak 1978, Stark et al. 1982, Akagi & Challis 1990). The magnitude of these changes varies at different gestational ages in relation to the progressive maturation of fetal HPA function. Thus, later in gestation, the plasma cortisol response to acute hypoxemia is enhanced, and the ACTH response diminished, presumably as a result of increased fetal adrenal respon- siveness, and greater negative feedback by the elevated basal and stimulated glucocorticoid concentrations (Norman et al. 1985, Akagi & Challis 1990). However, there is no information available concerning the effects of hypoxemia on levels of expression of key enzymes in the biosynthetic pathway of fetal adrenal glucocorticoids that might underlie these changes in plasma hormone concentrations. We have recently developed a model of prolonged (48 h) fetal hypoxemia without concurrent changes in fetal PaCO 2 or pH, to examine effects on fetal HPA function (Braems et al. 1996). To identify the gestational age- dependent changes, fetuses were studied on two occasions in late gestation, before and after day 130 of pregnancy (term 145 days), since this is a period of rapid change in HPA responsiveness. Hypoxemia produced similar changes in plasma immunoreactive (ir) ACTH in both groups of animals, but the change in plasma cortisol was greater and more sustained in the older fetuses. The objective of the present study was to determine whether the alteration of fetal adrenal function extended to C19 steroids, and whether age-dependent differences in 257 Journal of Endocrinology (1998) 159, 257–264  1998 Society for Endocrinology Printed in Great Britain 0022–0795/98/0159–257 $08.00/0