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Cortisol, epigenetics, FKBP5, intergenerational, PTSD, stress
Abstract:
BACKGROUND: The involvement of epigenetic mechanisms in
intergenerational transmission of stress effects has been demonstrated
in animals but not in humans.
METHODS: Cytosine methylation within the gene encoding for FK506 binding
protein 5 (FKBP5) was measured in Holocaust survivors (n = 32), their
adult offspring (n = 22), and demographically comparable parent (n = 8)
and offspring (n 5 9) control subjects, respectively.
Cytosine-phosphate-guanine sites for analysis were chosen based on their
spatial proximity to the intron 7 glucocorticoid response elements.
RESULTS: Holocaust exposure had an effect on FKBP5 methylation that was
observed in exposed parents as well in their offspring. These effects
were observed at bin 3/site 6. Interestingly, in Holocaust survivors,
methylation at this site was higher in comparison with control subjects,
whereas in Holocaust offspring, methylation was lower. Methylation
levels for exposed parents and their offspring were significantly
correlated. In contrast to the findings at bin 3/site 6, offspring
methylation at bin 2/sites 3 to 5 was associated with childhood physical
and sexual abuse in interaction with an FKBP5 risk allele previously
associated with vulnerability to psychological consequences of childhood
adversity. The findings suggest the possibility of site specificity to
environmental influences, as sites in bins 3 and 2 were differentially
associated with parental trauma and the offspring's own childhood
trauma, respectively. FKBP5 methylation averaged across the three bins
examined was associated with wake-up cortisol levels, indicating
functional relevance of the methylation measures.
CONCLUSIONS: This is the first demonstration of an association of
preconception parental trauma with epigenetic alterations that is
evident in both exposed parent and offspring, providing potential
insight into how severe psychophysiological trauma can have
intergenerational effects.
