Role of the hypothalamic-pituitary-adrenal axis in developmental programming of health and disease

Abstract

Adverse environments during the fetal and neonatal development period may permanently program physiology and metabolism, and lead to increased risk of diseases in later life. Programming of the hypothalamic-pituitary-adrenal (HPA) axis is one of the key mechanisms that contribute to altered metabolism and response to stress. Programming of the HPA axis often involves epigenetic modification of the glucocorticoid receptor (GR) gene promoter, which influences tissue-specific GR expression patterns and response to stimuli. This review summarizes the current state of research on the HPA axis and programming of health and disease in the adult, focusing on the epigenetic regulation of GR gene expression patterns in response to fetal and neonatal stress. Aberrant GR gene expression patterns in the developing brain may have a significant negative impact on protection of the immature brain against hypoxic-ischemic encephalopathy in the critical period of development during and immediately after birth.

Figure 1. The HPA components and feedback regulation of HPA activity

The AVP (arginine vasopressin) and CRH (corticotrophin-releasing hormone) produced from PVN of hypothalamus stimulate the synthesis and secretion of ACTH in anterior pituitary. The ACTH then promotes the production and release of GCs (glucocorticoids) from adrenal cortex. The HPA activity is controlled by negative feedback regulation of GCs at pituitary, PVN and limbic system level through effects of GR (glucocorticoid receptor) and MR (mineralocorticoid receptor). Adverse maternal environments can result in attenuated negative feedback regulation of HPA activity through decreased expression of GR in the hippocampus.

Figure 2. DNA methylation inhibits gene transcription

Transcription factors (TF) bind to corresponding binding sites on the GR (glucocorticoid receptor) promoter, and promote GR transcription. Methylation (red solid circles) modification of GR gene inhibits the transcription factor binding to the GR promoter, and leads to long-term silence of GR.

Figure 3. Structure of the human, mouse and rat GR genes and the potential mRNA transcripts

(A) scheme of the human, mouse and rat GR first exons. (B) potential mRNA transcripts of GR. Human GRα is encoded by exon2-8 and exon9α, GRβ by exon2-8 and exon9β, and GR-p by exon2-7. Mouse GRα is encoded by exon2-8 and exon9, while mouse GRβ is encoded by exon2-8 and a proximal portion of intron 8. Rats have only one GR isoform that is equivalent to human GRα.

Figure 4. Programming of the HPA axis and disease

Adverse maternal environments lead to increased exposure of the fetus to excess glucocorticoids and reset of the fetal HPA activity. Epigenetic regulation of GR (glucocorticoid receptor) plays a center role in this process. Programming of the HPA axis alters the gene expression patterns and/or permanently changes the organ structure, leading to various diseases in adulthood.