Epidemiological and experimental evidence suggests that an adverse fetal environment permanently “programmes” physiology leading to increased risks of cardiometabolic and neuropsychiatric disorders in later life. We originally hypothesised that fetal glucocorticoid overexposure might underpin this link. In genetically identical rodents, prenatal stress, glucocorticoid overexposure or inhibition/knockout of 11ß-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 HPA axis and metabolic programming. However, whilst first and second generation phenotypes are similar, the molecular mechanisms and epigenetic markers differ in each generation, implying strong selection on phenotype but weighing against neo-Lamarckian notions of ‘epigenetic inheritance’.
Glucocorticoid programming appears of clinical relevance. 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 or ingestion of liquorice (which inhibits 11β-HSD) alters offspring cognition, behaviour and HPA axis function. Stress has similar effects since the offspring of women pregnant during and directly exposed to the 9.11.2001 atrocity and who developed PTSD exhibit neuroendocrine changes but only if exposure was in the third trimester. Furthermore, exposure to the Nazi Holocaust exerted permanent effects upon glucocorticoid levels and steroid metabolism, effects dependent upon the age at exposure. The second (unexposed) generation also shows altered cortisol levels and metabolism, again with discordance in detail between generations. 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 these effects may impact on a subsequent generation. Any core mechanistic role for epigenetic processes in such early environment-induced effects is attractive but remains to be unequivocally established.Le texte complet de cet article est disponible en PDF.