Early life adversity is associated with both persistent disruptions in the hypothalamicpituitary-
adrenal (HPA) axis and psychiatric symptoms. Glucocorticoid receptors (GRs), which are
encoded by the NR3C1 gene, bind to cortisol and other glucocorticoids to create a negative feedback
loop within the HPA axis to regulate the body’s neuroendocrine response to stress. Excess methylation
of a promoter sequence within NR3C1 that attenuates GR expression, however, has been associated
with both early life adversity and psychopathology. As critical regulators within the HPA axis, GRs
and their epigenetic regulation may mediate the link between early life adversity and the onset of psychopathology.
The present review discusses this work as one mechanism by which stress may get under
the skin to disrupt HPA functioning at an epigenetic level and create long-lasting vulnerabilities in
the stress regulatory system that subsequently predispose individuals to psychopathology. Spanning
prenatal influences to critical periods of early life and adolescence, we detail the impact that early adversity
has on GR expression, physiological responses to stress, and their implications for long-term
stress management. We next propose a dual transmission hypothesis regarding both genomic and nongenomic
mechanisms by which chronic and acute stress propagate through numerous generations.
Lastly, we outline several directions for future research, including potential reversibility of methylation
patterns and its functional implications, variation in behavior determined solely by NR3C1, and
consensus on which specific promoter regions should be studied.
Keywords: NR3C1, HPA axis, Stress, Glucocorticoid receptor, Psychopathology, Methylation.
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