Glucocorticoid receptor gene (NR3C1) methylation during the first thousand days: Environmental exposures and developmental outcomes

The first 1000 days from conception are a sensitive period for human development programming. During this period, environmental exposures may result in long-lasting epigenetic imprints that contribute to future developmental trajectories. The present review reports on the effects of adverse and protective environmental conditions occurring during the first 1000 days on glucocorticoid receptor gene (NR3C1) regulation in humans. Thirty-four studies were included. Wide variations emerged for biological tissues, number and position of analyzed CpG sites, and age at methylation and outcomes assessment. Increased NR3C1 methylation associated with first 1000 days stress exposures. Maternal caregiving behaviors significantly buffered precocious stress exposures. A less robust pattern of findings emerged for the association of NR3C1 methylation with physical health, neurobehavioral and neuroendocrine outcomes. Although drawing comprehensive conclusions is partially hindered by methodological limitations, the present review underlines the relevance of the first 1000 days from conception as a time window for developmental plasticity. Prospective cohort studies and epigenome-wide approaches may increase our understanding of dynamics epigenetic changes and their consequences for child development.