Fetal Glucocorticoid Synthesis Is Required for Development of Fetal Adrenal Medulla and Hypothalamus Feedback Suppression

Abstract

During pregnancy, fetal glucocorticoid is derived from both maternal supply and fetal secretion. We have created mice with a disruption of the Cyp11a1 gene resulting in loss of fetal steroid secretion but preserving the maternal supply. Cyp11a1null embryos have appreciable although lower amounts of circulating corticosterone, the major mouse glucocorticoid, suggesting that transplacental corticosterone is a major source of corticosterone in fetal circulation. These embryos thus provide a means to examine the effect of fetal glucocorticoids. The adrenal in Cyp11a1 null embryos was disorganized with abnormal mitochondria and oil accumulation. The adrenal medullary cells did not express phenylethanolamine N-methyltransferase and synthesized no epinephrine. Cyp11a1 null embryos had decreased diencephalon Hsd11b1, increased diencephalon Crh, and increased pituitary Pomc expression, leading to higher adrenocorticotropin level in the plasma. These data indicate blunted feedback suppression despite reasonable amounts of circulating corticosterone. Thus, the corticosterone synthesized in situ by the fetus is required for negative feedback suppression of the hypothalamus-pituitary-adrenal axis and for catecholamine synthesis in adrenal medulla.

Maternal Immune Activation Produces Cerebellar Hyperplasia and Alterations in Motor and Social Behaviors in Male and Female Mice

“…In addition to causing elevations in pro-inflammatory cytokines, poly(I:C) activates the maternal hypothalamic pituitary axis and elevates corticosterone levels in rodents [97]. Inflammatory stimuli also elevate corticosterone during pregnancy [98], but it is unlikely that maternal corticosterone enters the fetal brain [99]. The placenta also expresses toll-like receptors (TLRs), including TLR3 [100], and there is evidence that inflammatory stimuli cause alterations in placental morphology [98] and function [96] that could have an impact upon the fetal environment, for example to cause hypoxia or other alterations.…”

Maternal Influences over Offspring Allergic Responses

“…In addition, it is reported that stress in adult 4-week-old mice exacerbates OVA-induced allergic responses and this stress-induced effect is blocked by pretreatment with a glucocorticoid receptor antagonist [103]. When maternal corticosterone is elevated during pregnancy, the maternal cortisol can cross the placenta and affect fetal cortisol levels [109, 110]. Others reported that maternal corticosterone crosses the placenta to the fetus and is a strong inducer of Th2 responses [111, 112].…”

Diethylstilbestrol decreased adrenal cholesterol and corticosterone in rats

“…Corticosterone, which is the principal glucocorticoid in rodents and is synthesised in the zona fasciculata (ZF), regulates metabolism, the stress response and immune function. In addition, adrenal steroids play important roles in foetal development and delivery (Chida et al 2011, Huang et al 2012. Therefore, the objective of this study is to investigate the interactions between endocrine disruptors and adrenal corticosterone synthesis suppression.…”