Elevation of 11β-hydroxysteroid dehydrogenase type 2 activity in Holocaust survivor offspring: evidence for an intergenerational effect of maternal trauma exposure

Abstract

Background: Adult offspring of Holocaust survivors comprise an informative cohort in which to study intergenerational transmission of the effects of trauma exposure. Lower cortisol and enhanced glucocorticoid sensitivity have been previously demonstrated in Holocaust survivors with PTSD, and in offspring of Holocaust survivors in association with maternal PTSD. In other work, reduction in the activity of the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD-2), which inactivates cortisol, was identified in Holocaust survivors in comparison to age-matched, unexposed Jewish controls. Therefore, we investigated glucocorticoid metabolism in offspring of Holocaust survivors to evaluate if similar enzymatic decrements would be observed that might help to explain glucocorticoid alterations previously shown for Holocaust offspring.

Methods: Holocaust offspring (n=85) and comparison subjects (n=27) were evaluated with clinical diagnostic interview and self-rating scales, and asked to collect a 24-h urine sample from which concentrations of cortisol and glucocorticoid metabolites were assayed by GCMS. 11β-HSD-2 activity was determined as the ratio of urinary cortisone to cortisol.

Results: Significantly reduced cortisol excretion was observed in Holocaust offspring compared to controls (p=.046), as had been shown for Holocaust survivors. However, 11β-HSD-2 activity was elevated for offspring compared to controls (p=.008), particularly among those whose mothers had been children, rather than adolescents or adults, during World War II (p=.032). The effect of paternal Holocaust exposure could not be reliably investigated in the current sample.

Conclusions: The inverse association of offspring 11β-HSD-2 activity with maternal age at Holocaust exposure is consistent with the influence of glucocorticoid programming. Whereas a long standing reduction in 11β-HSD-2 activity among survivors is readily interpreted in the context of Holocaust related deprivation, understanding the directional effect on offspring will require replication and further exploration.

Keywords: 11β-Hydroxysteriod dehydrogenase type 2; Biomarkers; Cortisol; Developmental programming; Glucocorticoid metabolism; HPA axis; Holocaust; Intergenerational; Offspring; PTSD.

Figure 1. Association of meternal age at Holocaust exposure with offspring 11β-HSD-2 activity

Mean 11β-HSD-2 activity for comparison subjects and Holocaust survivor offspring according to age of maternal Holocaust exposure (F_(3,90)= 3.07; p=.032, controlling for age and BMI). Bars represent estimated marginal means ± SE of raw data. * (p=.029)

Figure 2. Relation of 11β-HSD-2 activity to maternal exposure and PTSD status

Mean 11β-HSD-2 activity for comparison subjects and Holocaust survivor offspring according to maternal PTSD status (F_(2,90)=4.65, p=.012; controlling for age and BMI). Bars represent estimated marginal means ± SE of raw data. * (p=.009).

Figure 3. Association of maternal age at Holocaust exposure and maternal PTSD with offspring 11β-HSD-2 activity

Mean 11β-HSD-2 activity for comparison subjects and Holocaust survivor offspring according to both maternal age at Holocaust exposure (F_(3,85)=3.55, p=.018) and maternal PTSD status (F_(1,85)=2.13, ns) with no significant interaction between the two predictors (F_(2,85)=0.93, ns), controlling for age, gender, and BMI. Bars represent estimated marginal means ± SE of raw data. * (p=.021).