Intergenerational Effects of PTSD on Offspring Glucocorticoid Receptor Methylation

Posttraumatic stress disorder is precipitated by the experience of extreme stress in a subset of vulnerable individuals. Data now suggest that PTSD in parents confers vulnerability to PTSD in offspring. This is underlined by the observation that offspring born to individuals with PTSD exhibit low baseline cortisol levels, a neuroendocrine risk factor for PTSD. Several mechanisms have been proposed to mediate intergenerational inheritance of PTSD, including genetics and social learning. However, there is also the possibility that biological changes associated with PTSD in parents directly impact offspring, potentially via changes to gametes, fetuses in utero, or via changes in early postnatal care. The exact mechanism of this form of “intergenerational transmission” is unknown; however changes in epigenetic signatures, including DNA methylation, provide an appealing candidate. Animal studies have prompted investigation into methylation of the NR3C1 promoter, which regulates transcription of the glucocorticoid receptor gene. Here, we review evidence of NR3C1 methylation alterations in offspring of parents exposed to extreme stress and offspring of parents who developed PTSD in response to extreme stress. We propose several hypotheses based on the current evidence and suggest future directions related to these interpretations.