Inhibition of 11beta-hydroxysteroid dehydrogenase, the foeto-placental barrier to maternal glucocorticoids, permanently programs amygdala GR mRNA expression and anxiety-like behaviour in the offspring.
Glucocorticoids may underlie the association between prenatal stress, low birth weight and adult stress-associated disorders, e.g. hypertension and type 2 diabetes, increased hypothalamic-pituitary-adrenal (HPA) activity and affective dysfunction. Normally, 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) rapidly inactivates glucocorticoids in placenta and many foetal tissues, thus acting as a 'barrier' to maternal steroids. We investigated the effect of inhibiting foeto-placental 11beta-HSD in rats, using carbenoxolone (CBX), on subsequent HPA activity and regulation and stress-induced behaviour in adult offspring. Pregnant Wistar rats were injected with CBX (12.5 mg s.c.) or vehicle daily throughout pregnancy. CBX treatment reduced birth weight. Adult offspring of CBX-treated dams had persistently reduced body weight, increased basal corticosterone (CORT) levels, increased corticotropin-releasing hormone (CRH) and reduced glucocorticoid receptor (GR) mRNA in the hypothalamic paraventricular nucleus, though hippocampal GR and mineralocorticoid receptor (MR) mRNA expression were unaltered. In addition, these animals showed less grooming and rearing in an open field and reduced immobility in a forced swim test, and had increased GR mRNA expression in the basolateral (BLA), central (CEA) and medial (MEA) nuclei of the amygdala, with unaltered MR mRNA. These data suggest that disturbance of the foeto-placental enzymatic barrier to maternal glucocorticoids reduces birth and body weight, and produces permanent alterations of the HPA axis and anxiety-like behaviour in aversive situations. The behavioural and HPA effects may reflect GR gene programming in amygdala and hypothalamus, respectively. Foetal overexposure to endogenous glucocorticoids (prenatal stress or reduced activity of foeto-placental 11beta-HSD) may represent a common link between the prenatal environment, foetal growth and adult neuroendocrine and affective disorders.
Welberg
L A
LA
Molecular Endocrinology Laboratory, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, Scotland.
Seckl
J R
JR
Holmes
M C
MC
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001007:Anxiety / Q000139:chemically induced / Q000523:psychology*; D001522:Behavior, Animal / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D002229:Carbenoxolone / Q000494:pharmacology; D003345:Corticosterone / Q000378:metabolism; D003863:Depression / Q000523:psychology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005938:Glucocorticoids / Q000378:metabolism*; D006913:Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology; D017403:In Situ Hybridization; D008431:Maternal-Fetal Exchange / Q000187:drug effects*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis* / Q000187:drug effects; D013550:Swimming / Q000523:psychology
D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; D002229:Carbenoxolone; D003345:Corticosterone