The impact of the periconceptional and preimplantation environment on adrenal development and steroidogenesis in the fetal sheep.

Abstract

Experimental and clinical studies provide evidence that perturbations and manipulation of the in vivo and ex vivo nutritional environment during the periconceptional period alters the development of the fetal hypothalamo-pituitaryadrenal (HPA) axis and gestation length. In particular periconceptional maternal undernutrition results in an earlier prepartum activation of the fetal HPA axis and adrenal development whereas culturing embryos in vitro in the presence of human serum is associated with delayed parturition in the sheep. It is not clear, however, whether the effects resulting from periconceptional undernutrition are due to the impact of undernutrition acting on the development of both the oocyte and embryo or on just the early embryo. It is also not known how culturing embryos in vitro in the absence or presence of human serum impacts on the prepartum activation of the HPA axis and adrenal development. Lastly, the intra-adrenal molecular mechanisms by which changes in the in vivo or in vitro nutritional environment of the early embryo alter HPA development have not been fully investigated. This thesis provides evidence for the first time which suggests that periconceptional undernutrition may differentially target components of the fetal HPA axis depending on exposure to undernutrition during specific periconceptional time periods. Specifically, periconceptional undernutrition alters fetal adrenal growth and development whilst undernutrition during the preimplantation period alone is sufficient to alter the development of the fetal anterior pituitary in late gestation. A further novel finding of this thesis is that when embryos were cultured in vitro in a defined medium fetal plasma ACTH concentration significantly increased in singletons whereas relative adrenal weight and adrenal CYP17 mRNA expression significantly increased in both singleton and twins in late gestation. This suggests that this embryo culture system affects adrenal growth and development, independent of fetal number and importantly, that there is an early activation of the HPA axis in the singleton fetus in late gestation. Interestingly, addition of serum to the in vitro culture media reverses the effects of culturing embryos in vitro in the absence of serum and the mechanism(s) by which restoration of fetal adrenal development occurs may involve the intra-adrenal IGF system. In summary, alteration of the development of the fetal HPA axis appears to be dependent on specific periconceptional time windows of poor nutritional exposure and type of culture media to which an embryo is exposed to.