Effect of Maternal Periconceptional Undernutrition in Sheep on Cortisol Regulation in Offspring from Mid-late Gestation, Through to Adulthood

Introduction: Maternal periconceptional undernutrition (PCUN) alters fetal hypothalamic-pituitary-adrenal axis (HPAA) function and placental glucocorticoid metabolism in sheep. The effects of PCUN on HPAA function in adult life are not known. We investigated the effects of PCUN on fetal adrenal development across gestation and on cortisol regulation in adult offspring.

Methods: Ewes were undernourished from 61 days before to 30 days after conception ('PCUN') or fed ('N'). mRNA expression in the fetal adrenal gland of ACTH receptor (), steroidogenic acute regulatory protein (, cytochrome P450 17A1 (, 11beta-hydroxysteroid-dehydrogenase type 2 (, insulin-like growth factor-2 (, and in the fetal hippocampus of , , mineralocorticoid receptor () and glucocorticoid receptor () was determined at 50 (adrenal only), 85, 120 and 131 days of gestation (term=148 days). In adult offspring (≥ 3 years, N; 10 female, 5 male, PCUN; 10 female, 10 male) a combined arginine vasopressin (AVP, 0.1 μg/kg) and corticotropin-releasing hormone (CRH, 0.5 μg/kg) challenge and a metyrapone (40 mg/kg) challenge were undertaken. mRNA expression of , and were determined in adult adrenals.

Results: Fetal adrenal , and mRNA expression were not different between groups in early gestation but were higher in PCUN than N at 131 days' gestation (all <0.01). PCUN reduced fetal hippocampal and mRNA expression by 50% at 85 day, but not in later gestation. Adult offspring plasma cortisol responses to AVP+CRH or metyrapone were not different between groups. Plasma ACTH response to AVP+CRH was lower in PCUN males but ACTH response to metyrapone was not different between groups. Adult adrenal , , and mRNA expression were not affected by PCUN.

Conclusions: We conclude that the effects of PCUN on fetal HPAA function that became apparent in late gestation, are not reflected in adrenal cortisol secretion in mid-adulthood.