Endocrine Abstracts

Maternal programming increases the risk of alterations in the offspring’s HPA axis. Previously we showed that maternal undernutrition in sheep induces epigenetic changes in the glucocorticoid receptors (GR) within hypothalamic energy balance pathways, without affecting HPA axis GR. However, these studies focussed on fetal tissues¹. Here, we investigated whether GR is epigenetically altered in the HPA axis of adult offspring to determine the status of the pathways in adult life.

Ewes were maternally undernourished from 60 days before until 30 days after conception (UN) or fed ad libitum (N). Term =148 days. Brain tissue from adult offspring (mean age 4.4 years) were collected for analysis.

Hippocampal GR mRNA expression was decreased in female and male UN offspring (27% (P<0.03) and 28% (P<0.02) respectively) compared with controls. Similarly, GR protein levels were decreased in UN offspring (UN females; 64%, (P<0.02): UN males 40% (P<0.004)). Epigenetic analysis found a 50% increase in GR promoter methylation in UN females (P<0.02) but not in males. However, changes in epigenetic histone markers (H3K9 acetylation and H3K27 trimethylation) associated with the GR promoter were found in both males and females, consistent with GR expression data.

Within the pituitary, epigenetic changes in GR were gender specific. These were associated with decreased GR mRNA and protein in UN females (mRNA: 39% (P<0.01); protein: 43% (P<0.04)) and increased GR mRNA and protein in UN males (mRNA: 94% (P<0.05); protein: 118% (P<0.004)) compared with controls.

These studies in adult offspring find changes in the epigenetic and expression status of GR in the HPA axis not found at the fetal stage that were both tissue and gender specific. Therefore, maternal undernourishment during pregnancy results in alterations in the HPA axis which are manifest in adult sheep, suggesting plasticity in the effects of programming.

1. Stevens et al. Endocrinology 2010 8 3652–3664.

Declaration of funding

The work was supported by the UK National Institute of Health Research Manchester Biomedical Research Center, the Health Research Council of New Zealand, the New Zealand National Research Centre for Growth and Development, and the Canadian Institutes for Health Research.