Endocrine Abstracts (2009) 20 S6.1

Glucocorticoids and developmental programming

Jonathan Seckl

University of Edinburgh, Edinburgh, UK.

Epidemiological evidence suggests that an adverse fetal environment permanently programmes physiology leading to increased risks of cardiometabolic, neuroendocrine and psychiatric disorders in adulthood. We originally hypothesised that prenatal stress via fetal glucocorticoid excess might explain this link. Indeed, in rodents, prenatal stress, glucocorticoid exposure or inhibition/knockout of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), the feto-placental ‘barrier’ to maternal glucocorticoids, reduces birth weight and causes permanent hypertension, hyperglycaemia, increased hypothalamic–pituitary–adrenal (HPA) axis activity and anxiety-related behaviours in adult offspring. The phenotype persists into a second generation and transmits via male and female lines. This implies epigenetic mediation, a mechanism emerging for at least HPA axis programming. This also appears of potential clinical relevance. Thus, in a singleton-bearing, non-human primate model, exposure to glucocorticoids in the second half of gestation programmes cardiometabolic, HPA and behavioural parameters in 1-year old offspring. In humans, placental 11β-HSD2 activity correlates directly with birth weight and inversely with infant blood pressure. Moreover, low birth weight babies have higher plasma cortisol levels throughout adult life, indicating HPA programming. Indeed, maternal glucocorticoid therapy alters offspring cognition and affect, and pregnant women exposed to the 9.11.2001 atrocity and who developed PTSD appear to transmit neuroendocrine changes to their one-year old offspring, but confined to third trimester exposure. Furthermore, exposure to the Nazi Holocaust exerted permanent effects upon glucocorticoid levels and steroid metabolism, effects dependent upon the age at exposure. Second generation effects also occur. Overall, the data suggest that developmental exposure to excess glucocorticoids/stress programmes peripheral and CNS functions in adult life, predisposing to affective and other pathology, and may be transmitted into at least one subsequent generation.

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