Effect of periconceptional undernutrition and gender on hypothalamic–pituitary–adrenal axis function in young adult sheep

Abstract

Glucocorticoids are proposed to act as intermediary factors that transcribe the developmental programming sequelae of maternal nutrient restriction (NR). Periconceptional under-nutrition of sheep markedly activates fetal hypothalamic-pituitary-adrenal (HPA) axis activity leading to preterm birth, while transient undernutrition during late gestation in sheep programs adult HPA axis function. To date, no study has examined resting or stimulated HPA axis function in young adult offspring following a periconceptional nutritional challenge. In the present study, 20 ewes were either periconceptionally undernourished (50% metabolisable energy requirements from days 1 to 30 gestation; NR, n = 8) or fed to control levels (100% requirement; controls, n = 12) to term (147 days gestation). Ewes were blood sampled remotely at 2 and 30 days using automated blood sampling equipment. Thereafter, offspring (controls, n = 6/6 males/females; NR, n = 4/4 males/females) were reared to 1 year of age and on separate days received either an i.v. corticotrophin-releasing hormone (CRH; 0.5 microg/kg) and vasopressin (AVP; 0.1 microg/kg) challenge or a synthetic ACTH i.v. bolus (Synacthen; 1.25 microg/kg), and blood samples were taken (manually and remotely) at appropriate intervals for measurement of plasma ACTH and cortisol accordingly. Resting plasma cortisol, assessed remotely, was similar in ewes during undernutrition (control 18.3 +/- 1.4 vs NR 23.4 +/- 1.9 nmol/l) and in offspring at 4 months of age (control male 17.6 +/- 2.9; control female 17.2 +/- 0.4, NR male 16.5 +/- 3.1, NR female 21.7 +/- 4.0 nmol/l). At 12 months of age, however, resting plasma cortisol was significantly increased in NR females (control male 28.0 +/- 1.5, control female 32.9 +/- 9, NR male 32 +/- 7, NR female 53 +/- 10 nmol/l, F 5.7, P = 0.02) despite no difference in plasma ACTH concentration. There was an interaction between nutritional group and gender for both the pituitary and adrenal responses to CRH and AVP, i.e. for controls, females exhibited increased plasma ACTH or cortisol relative to males but for NR this trend was either not present or reversed. The adrenocortical response to synthetic ACTH was gender-dependent only, being greater in female offspring. Combined CRH and AVP provoked a transient hypertension and marked bradycardia in all animals, irrespective of dietary group or gender and could be effectively reproduced by an AVP bolus alone. In conclusion, the present study has shown that periconceptional undernutrition of sheep has only a minor influence on HPA axis function in their young adult offspring when considered alongside the effect of gender per se.