Stress during pregnancy programs long-term health outcomes. The hypothalamic-pituitary-adrenal-(HPA) axis plays a central role in regulating disease outcomes, but the impact of increased endogenous glucocorticoid concentrations on the structure and function of offspring adrenal glands has not been thoroughly investigated. This study aimed to identify the effects of short-term, prenatal corticosterone (Cort) exposure in the mouse on offspring adrenal gland morphology and steroid hormone concentrations.
Cort was administered to C57Bl/6 mice via osmotic minipump (33mg/kg/h) for 60h from E12.5. Adrenals and plasma were collected from offspring at PN30 (adolescent), 6 months (adult) and 12 months (aged). Adrenals were fixed and processed for histological/volume analysis or frozen for qPCR analysis of steroidogenic enzymes (Cyp11a1, Cyp21a1, Cyp11b1, Hsd11b2, Cyp11b2), cholesterol transport protein (Star) and ACTH receptor (Mc2r). Plasma Cort was measured by RIA and aldosterone by ELISA. Adrenal volumes were determined by stereological analysis using the Cavalieri method.
Prenatal Cort had no effect on adrenal parameters measured in females at any age. In males, adrenal weight was unaffected at PN30 but increased at 6 months (44%). Plasma Cort levels were similar between Cort and Untr animals at PN30 but Cort (71%) and aldosterone (44%) were both increased in 6 month-old male offspring. Adrenal volume was reduced in Cort-exposed male offspring at PN30, particularly in the zona fasciculata (36%) which contains the glucocorticoid-producing cells, but was increased by 6 months (52%). Interestingly, Mc2r was up-regulated (1.2-fold) at PN30 and Cyp11a1 was down-regulated (1.4-fold) at 6 months in Cort-exposed male offspring. At 12 months, Cort-exposed male mice showed enhanced age-induced plaque formation and fibrosis.
Prenatal Cort results in age-dependent changes to adrenal size, volume and steroidogenic gene expression in male offspring while females appeared unaffected. These findings suggest a role for the HPA in the etiology of sex-specific programming of disease.