Differential regulation of proopiomelanocortin messenger ribonucleic acid in the pars distalis and pars intermedia of the pituitary gland after prolonged hypoxemia in fetal sheep.

Abstract

POMC messenger RNA (mRNA) is synthesized and translated to form ACTH in the pars distalis and ACTH-related peptides in the pars intermedia of the pituitary in fetuses of species such as sheep. In the fetal sheep, maturation of hypothalamo-pituitary-adrenal (HPA) function occurs during late pregnancy accompanied by increased levels of POMC mRNA in the pars distalis, and contributes to the stimulus for birth. Activation of fetal HPA function also occurs with short term hypoxemia. However, the effects of more prolonged fetal hypoxemia, which may predispose to premature parturition, on POMC mRNA levels in the pars distalis and pars intermedia are not known. We studied the effects of sustained hypoxemia (48 h) in the absence of acidosis on fetal HPA responses at two times in late gestation, days 126-130 and days 134-136 (term = approximately 145 days). Hypoxemia was induced by lowering the fraction of oxygen in the maternal inspired gas mixture. Fetal arterial oxygen tension fell by 6-8 mm Hg, without a change in fetal arterial pH or carbon dioxide tension. Pituitary POMC mRNA was localized and quantified by in situ hybridization. At both gestational ages, hypoxemia caused a transient elevation in fetal plasma ACTH, with a maximum response at +2 h, and a sustained elevation in circulating cortisol. Cortisol responses were greater in the older fetuses. Changes in plasma cortisol were not associated with alterations in the plasma corticosteroid-binding capacity or in levels of hepatic corticosteroid-binding globulin mRNA. Pituitary POMC mRNA showed a regional distribution in the pars distalis, and mean levels increased with gestational age. After 48 h of hypoxemia, POMC mRNA levels had increased in the pars distalis. The regional distribution was unaffected by the hypoxemic insult. In contrast, POMC mRNA levels in the pars intermedia decreased after hypoxemia, and the reduction was greater in the older fetuses. We conclude that in response to prolonged hypoxemia, there is differential regulation of POMC mRNA levels in the pars distalis and pars intermedia of the pituitary in fetal sheep. The magnitude of these responses also changes with gestational age. The increase in POMC mRNA levels in the pars distalis at 48 h of hypoxemia, despite a rise in plasma cortisol and without a change in corticosteroid-binding globulin, suggests altered regulation of HPA function at this time.

Development of baroreflex and endocrine responses to hypotensive stress in newborn foals and lambs

“…Although differential expression and regulation of proopiomelanocortin within the pars distalis and pars intermedia [29], and of insulin-like growth factors between the anterior and posterior pituitary lobes [30] have been described in the sheep, there is no information on differential maturation of the pituitary lobes in the horse. Furthermore, AVP is known to synergise with CRH in the control of pituitary ACTH secretion in both fetal sheep [31] and adult horses [32] in response to specific stimuli.…”

Leptin receptor antagonist treatment ameliorates the effects of long-term maternal hypoxia on adrenal expression of key steroidogenic genes in the ovine fetus

“…Acute hypoxia is normally considered a potent activator of the fetal HPA axis, leading to acutely increased cortisol production, and during late gestation, moderate sustained hypoxia (hours to a few days) leads to activation and accelerated maturation of the fetal HPA axis (5,6,22). However, we have found that development under conditions of moderate long-term hypoxia (LTH) in sheep results in significant alterations in HPA axis function by late gestation (1,15,27,28).…”

Gene expression following fetal hypoxemia

“…Man muss davon ausgehen, dass die kurzfristige ACTH-Stimulation bei den älteren hypoxämischen Feten zu einer endgültigen Erhöhung der Cortisolproduktion führte [2]. Bei den hypoxämischen Feten stieg die Plasma-ACTH-Konzentration direkt nach Beginn der Hypoxämie um ein Vielfaches an (Abb.…”

“…Durch die Freisetzung von ACTH und die gleichzeitige Abnahme der ACTH-Intermediäre wird nicht nur die immunreaktiv gemessene ACTH-Konzentration, sondern auch die biologische Aktivität von ACTH erhöht, da jetzt mehr freie ACTH-Rezeptoren in der Nebennierenrinde zur Verfügung stehen [2]. Bei einer Verschlechterung der Hypoxämie könn-te der fetale Organismus nochmals größere Mengen an ACTH freisetzen, welches die wesentliche Antwort auf den hypoxämischen Stress darstellt.…”

“…Bedingungen Material verschiedener Organe für Immunhistochemie, Northern-blot-Analyse und In-situ-Hybridisierung entnommen [2]. Die exogene Gabe von adrenocorticotropem Hormon (ACTH) führt beim fetalen Schaf jedoch zu einem vorzeitigen Einsetzen der Wehentätigkeit.…”