Epigenetic effects of glucocorticoids.

The early nurturing environment has persistent influences on developmental programming of inter-individual differences in metabolic and endocrine function that contribute to emotional and cognitive performance through life. These effects are mediated, in part, through neonatal programming of hypothalamic-pituitary-adrenal (HPA) axis function. Animal models support this hypothesis. For example, in the rat natural variations in maternal care influence HPA axis stress reactivity in the offspring via long-term changes in tissue-specific gene expression. Studies in vivo and in vitro show that maternal licking and grooming increases glucocorticoid receptor expression in the offspring via increased hippocampal serotonergic tone accompanied by increased histone acetylase transferase activity, histone acetylation and DNA demethylation mediated by the transcription factor nerve growth factor-inducible protein-A. These effects are reversed by early postnatal cross-fostering and by pharmacological manipulations, including trichostatin A (TSA) and l-methionine administration in adulthood. These studies demonstrate that an epigenetic state of a gene can be established through early in life experience, and is potentially reversible in adult life. Accordingly, epigenetic modifications in target gene promoters in response to environmental demand may ensure stable yet dynamic regulation that mediates persistent changes in biological and behavioral phenotype over the lifespan.